JP2022525425A - Avilaterone-Cyclic oligomer pharmaceutical preparation and its formation method and administration method - Google Patents

Abstract

The present disclosure discloses a pharmaceutical preparation containing an avilateron and a cyclic oligomer, and a tablet containing such a pharmaceutical preparation, a method for forming such a pharmaceutical preparation, and a method for administering such a pharmaceutical preparation or tablet. Regarding.

Description

Priority Claim This application benefits from the priority of US Provisional Application No. 62 / 820,076 filed March 18, 2019 and US Provisional Application No. 62 / 942,111 filed November 30, 2019. The entire contents of both applications are incorporated herein by reference.

Technical Fields The present disclosure relates to abiraterone pharmaceutical formulations and methods of forming and administering such pharmaceutical formulations.

Background Certain types of advanced prostate cancer are often difficult to treat because androgens cause cancer cell proliferation. Androgens are produced primarily in the testes of adult men, but also from the adrenal glands and, in the case of some prostate cancers, from the cancer cells themselves. As a result, some advanced prostate cancers continue to show androgen-induced growth even after the patient is castrated. Abiraterone blocks androgen production and specific testosterone production in the testes, adrenal glands, and the cancer cells themselves. Therefore, orally administered abiraterone acetate is approved for use in patients with metastatic castration-resistant prostate cancer (mCRPC). In addition, abiraterone has shown potential efficacy in the treatment of other androgen-sensitive cancers, such as breast cancer.

Abiraterone blocks androgen biosynthesis by inhibiting cytochrome P450 17A1 (CYP17A1). As a result, patients taking abiraterone may experience inadequate glucocorticoid levels, eg, low serum cortisol and systemic adverse effects of compensatory adrenocorticotropic hormone increases. Therefore, patients taking abiraterone are typically given glucocorticoid replacement therapy.

Abiraterone is highly lipophilic and has low water solubility in the gastrointestinal tract, thus severely limiting the oral bioavailability of the drug. The main commercial product, Zytiga, alleviates this insolubility problem by using abiraterone acetate, a more soluble ester prodrug. However, the effectiveness of prodrugs for improving bioavailability is limited, as evidenced by the food effect and pharmacokinetic variability cited on the label. Specifically, the absolute bioavailability of abiraterone is up to 10% when Zytiga is given according to the label (fasting), as AUC increases 10-fold when Zytiga is given with a high-fat diet. Is suggested. In addition, exposure did not increase significantly when the Zytiga dose was doubled from 1,000 mg to 2,000 mg (8% average AUC increase). The results of this study mean that Zytiga was dosed near the absorption limit.

In the treatment of metastatic castration-resistant prostate cancer with abiraterone, a decrease in prostate-specific antigen (PSA) heralds improved clinical outcomes. In well-managed trials, daily dosing of 1,000 mg abiraterone acetate reduces target PSA by only up to 60% of treated patients. Therefore, abiraterone is still a difficult drug to administer optimally.

In addition, recent findings suggest that abiraterone response in patients with metastatic castration-resistant prostate cancer correlates with steady-state trough levels (C _min ) (Xu et al., Clin. Pharmacokinet. 56). : 55-63, 2017 (Non-Patent Document 1)). More specifically, C _min values greater than about 30 ng / mL correlate with a large decay rate. This suggests that improving avilateron bioavailability and optimizing the pharmacokinetic profile lead to improved therapeutic efficacy, i.e., antitumor response. This finding indicates that the therapeutic benefit of Zytiga is limited by sub-optimal abiraterone delivery, with improved abiraterone compositions, in particular abiraterone compositions that can increase systemic abiraterone exposure and trough levels. It sheds light on what is much needed.

Xu et al., Clin. Pharmacokinet. 56: 55-63, 2017

Summary The present disclosure provides pharmaceutical formulations containing abiraterone and cyclic oligomer excipients.

を有する、少なくとも99％のアビラテロンを含んでもよい;
iv)アビラテロンは少なくとも99％のアビラテロン塩を含んでもよい;
v)アビラテロンは少なくとも99％のアビラテロンエステルを含んでもよい;
v-a)アビラテロンエステルは、以下の構造式:

を有する、酢酸アビラテロンを含んでもよい;
vi)アビラテロンは少なくとも99％のアビラテロン溶媒和化合物を含んでもよい;
vii)アビラテロンは少なくとも99％のアビラテロン水和物を含んでもよい;
viii)薬学的製剤は10mg、25mg、50mg、70mg、100mg、または250mgのアモルファスアビラテロンを含んでもよい;
ix)薬学的製剤は、空腹時に摂取された時の50mg、70mg、100mg、250mg、500mg、もしくは1000mgの結晶性アビラテロンもしくは結晶性酢酸アビラテロンと同じかまたはそれより大きな治療効果、バイオアベイラビリティ、C_min、C_max、もしくはT_maxを患者において実現するのに十分な量のアモルファスアビラテロンまたはその塩を含んでもよい;
x)薬学的製剤は10mg、25mg、50mg、70mg、100mg、250mg、または500mgの量のアモルファスアビラテロンまたはその塩を含んでもよい;
xi)薬学的製剤は、空腹時に摂取された時の10mg、25mg、50mg、70mg、100mg、250mg、500mgもしくは1000mgの結晶性アビラテロンもしくは結晶性酢酸アビラテロンと同じかまたはそれより大きな治療効果、バイオアベイラビリティ、C_min、C_max、もしくはT_maxを患者において実現するのに十分な量のアモルファスアビラテロンまたはその塩を含んでもよい;
xii)薬学的製剤は1,000mgのアモルファスアビラテロンまたはその塩を含んでもよい;
xiii)薬学的製剤は、空腹時に摂取された時の1,000mgの結晶性アビラテロンもしくは結晶性酢酸アビラテロンと同じかまたはそれより大きな治療効果、バイオアベイラビリティ、C_min、C_max、もしくはT_maxを患者において実現するのに十分な量のアモルファスアビラテロンまたはその塩を含んでもよい;
xiv)アビラテロンまたはその塩と環状オリゴマーは1:0.25～1:25のモル比で存在してもよい;
xv)アビラテロンまたはその塩と環状オリゴマーは少なくとも1:2のモル比で存在してもよい;
xvi)薬学的製剤は1重量％～50重量％のアモルファスアビラテロンまたはその塩を含んでもよい;
xvii)薬学的製剤は少なくとも10重量％のアモルファスアビラテロンまたはその塩を含んでもよい;
xviii)環状オリゴマー賦形剤は環状オリゴ糖または環状オリゴ糖誘導体を含んでもよい;
xvii-a)環状オリゴ糖または環状オリゴ糖誘導体はシクロデキストリンまたはシクロデキストリン誘導体を含んでもよい;
xvii-a-a)シクロデキストリン誘導体はヒドロキシプロピルβシクロデキストリンを含んでもよい;
xvii-a-b)シクロデキストリン誘導体はナトリウム(Na)スルホ-ブチルエーテルβシクロデキストリンを含んでもよい;
xvii-a-c)シクロデキストリン誘導体はヒドロキシプロピル基を含んでもよい;
xvii-a-d)シクロデキストリン誘導体はスルホ-ブチルエーテル官能基を含んでもよい;
xvii-a-e)シクロデキストリン誘導体はメチル基を含んでもよい;
xvii-a-f)シクロデキストリン誘導体はカルボキシメチル基を含んでもよい;
xix)薬学的製剤は50重量％～99重量％の環状オリゴマー賦形剤を含んでもよい;
xx)薬学的製剤は少なくとも90重量％の環状オリゴマー賦形剤を含んでもよい;
xxi)薬学的製剤はさらなる賦形剤を含んでもよい;
xxi-a)環状オリゴマー賦形剤は一次賦形剤でもよい;
xxi-b)さらなる賦形剤は一次賦形剤でもよい;
xxi-b-a)さらなる賦形剤は二次賦形剤でもよい;
xxi-c)さらなる賦形剤はポリマー賦形剤でもよい;
xxi-c-a)ポリマー賦形剤は水溶性でもよい;
xxi-c-b)ポリマー賦形剤は非イオン性ポリマーを含んでもよい;
xxi-c-c)ポリマー賦形剤はイオン性ポリマーを含んでもよい;
xxi-c-d)ポリマー賦形剤はヒドロキシプロピルメチルセルロースアセテートスクシネートを含んでもよい;
xxi-c-d-a)ヒドロキシプロピルメチルセルロースアセテートスクシネートは5～14％アセテート置換および4～18％スクシネート置換を有してもよい;
xxi-c-d-a-a)ヒドロキシプロピルメチルセルロースアセテートスクシネートは10～14％アセテート置換および4～8％スクシネート置換を有してもよい;
xxi-c-d-a-a-a)ヒドロキシプロピルメチルセルロースアセテートスクシネートは12％アセテート置換および6％スクシネート置換を有してもよい;
xxi-d)薬学的製剤は1重量％～49重量％のさらなる賦形剤を含んでもよい;
xxi-e)薬学的製剤は10重量％以下のさらなる賦形剤を含んでもよい;
xxii)薬学的製剤はグルココルチコイド補充(glucocorticoid replacement)APIを含んでもよい;
xxii-a)グルココルチコイド補充APIはプレドニゾン、メチルプレドニゾン、プレドニゾロン、メチルプレドニゾロン、デキサメタゾン、またはそれらの組み合わせを含んでもよい;
xxiii)薬学的製剤は、空腹時に摂取された時の等量の結晶性アビラテロンまたは結晶性酢酸アビラテロンの少なくとも6倍のC_max増加を患者において実現するのに十分な量のアモルファスアビラテロンまたはその塩を含んでもよい;
xxiv)薬学的製剤は、空腹時に摂取された時の等量の結晶性アビラテロンまたは結晶性酢酸アビラテロンの少なくとも3倍のAUC_0-t増加を患者において実現するのに十分な量のアモルファスアビラテロンまたはその塩を含んでもよい;
xxv)薬学的製剤は、空腹時に摂取された時の等量の結晶性アビラテロンまたは結晶性酢酸アビラテロンの少なくとも6％のC_maxばらつき減少を患者において実現するのに十分な量のアモルファスアビラテロンまたはその塩を含んでもよい。
xxvi)薬学的製剤は、空腹時に摂取された時の等量の結晶性アビラテロンまたは結晶性酢酸アビラテロンの少なくとも4％のAUC_0-tばらつき減少を患者において実現するのに十分な量のアモルファスアビラテロンまたはその塩を含んでもよい。
xxvii)薬学的製剤は、空腹時に摂取された時の等量の結晶性アビラテロンまたは結晶性酢酸アビラテロンの少なくとも25％のC_maxばらつき減少を、摂食状態で摂取された時の患者において実現するのに十分な量のアモルファスアビラテロンまたはその塩を含んでもよい。
xxviii)薬学的製剤は、空腹時に摂取された時の等量の結晶性アビラテロンまたは結晶性酢酸アビラテロンの少なくとも23％のAUC_0-tばらつき減少を、摂食状態で摂取された時の患者において実現するのに十分な量のアモルファスアビラテロンまたはその塩を含んでもよい;
xxix)薬学的製剤は、絶食状態で摂取された時のCmaxと比較して、摂食状態で摂取された時に、30％未満のCmax変動を実現するのに十分な量のアモルファスアビラテロンまたはその塩を含んでもよい;
xxx)薬学的製剤は、絶食状態で摂取された時のAUC_0-tと比較して、摂食状態で摂取された時の患者において10％未満のAUC_0-t変動を実現するのに十分な量のアモルファスアビラテロンまたはその塩を含んでもよい;
xxxi)薬学的製剤は、1日1回、1日2回、1日3回、または1日4回投与された時にヒト患者集団において少なくとも35ng/mLの平均C_minを実現するのに十分な量のアモルファスアビラテロンまたはその塩を含んでもよい。
xxxii)薬学的製剤は、絶食状態で摂取された時の等量もしくはそれより多い量の結晶性アビラテロンまたは等量もしくはそれより多い量の結晶性酢酸アビラテロンと比較して増加した治療効果、バイオアベイラビリティ、Cmin、またはCmaxを、転移性去勢抵抗性前立腺癌および一次耐性がある患者において実現するのに十分な量のアモルファスアビラテロンまたはその塩を含んでもよい;
xxxiii)薬学的製剤は、絶食状態で摂取された時の等量もしくはそれより多い量の結晶性アビラテロンまたは等量もしくはそれより多い量の結晶性酢酸アビラテロンと比較して増加した治療効果、バイオアベイラビリティ、Cmin、またはCmaxを、転移性去勢抵抗性前立腺癌および獲得耐性(acquired resistance)がある患者において実現するのに十分な量のアモルファスアビラテロンまたはその塩を含んでもよい;
xxxiv)薬学的製剤は、絶食状態で摂取された時の等量もしくはそれより多い量の結晶性アビラテロンまたは等量もしくはそれより多い量の結晶性酢酸アビラテロンと比較して増加した治療効果、バイオアベイラビリティ、Cmin、またはCmaxを、トリプルネガティブ乳癌がある患者において実現するのに十分な量のアモルファスアビラテロンまたはその塩を含んでもよい;
xxxv)薬学的製剤は、絶食状態で摂取された時の等量もしくはそれより多い量の結晶性アビラテロンまたは等量もしくはそれより多い量の結晶性酢酸アビラテロンと比較して増加した治療効果、バイオアベイラビリティ、Cmin、またはCmaxを、非転移性去勢抵抗性前立腺癌がある患者において実現するのに十分な量のアモルファスアビラテロンまたはその塩を含んでもよい。
xxxvi)薬学的製剤は、アモルファスアビラテロンと環状オリゴマー賦形剤を含む包接錯体(inclusion complex)を含んでもよい。
xxxvi-a)包接錯体を含む薬学的製剤は、30重量％まで、20重量％まで、または10重量％までのアモルファスアビラテロンを含んでもよい。
xxxvi-b)包接錯体を含む薬学的製剤は10重量％までのアモルファスアビラテロンを含んでもよい。
xxxvi-c)包接錯体を含む薬学的製剤は、熱力学的配合(thermokinetic compounding)を含む方法によって形成されてもよい。
xxxvi-d)アモルファスアビラテロンの少なくとも90％、91％、92％、93％、94％、95％、96％、97％、98％、99％、または99.9％が包接錯体に存在してもよい。
xxxvi-e)薬学的製剤を、結晶型アビラテロンの融点の90％までの温度まで加熱し、薬学的製剤を室温まで冷却させることに応答して、アビラテロンの10％未満、9％未満、8％未満、7％未満、6％未満、5％未満、4％未満、3％未満、2％未満、1％未満、または0.1％未満が結晶型をとってもよい。
xxxvi-e-i)結晶型をとるアビラテロンの10％未満、9％未満、8％未満、7％未満、6％未満、5％未満、4％未満、3％未満、2％未満、1％未満、または0.1％未満が、X線回折を含む方法によって確かめられてもよい。
xxxvi-f)包接錯体を含む薬学的製剤は、0.01N HCl、ならびに模擬胃液(Simulated Gastric Fluid)(SGF)、絶食時模擬腸液(Fasted State Simulated Intestinal Fluid)(FaSSIF)、および摂食時模擬腸液(Fed State Simulated Intestinal Fluid)(FeSSIF)より選択される生体関連媒液のうちの少なくとも1つの中での溶出により証明された時、純粋(neat)結晶性アビラテロンを含有する薬学的製剤よりも、患者の胃腸管内で少なくとも13～17倍増加した溶出を有してもよい。
xxxvi-g)包接錯体を含む薬学的製剤は、空腹時に摂取された時、より多い量の結晶性アビラテロンまたは結晶性酢酸アビラテロンと比較して、患者におけるアビラテロンのバイオアベイラビリティにおいて4倍までの増加を有してもよい。 According to various further embodiments of pharmaceutical formulations, all of which can be combined with each other, unless they are clearly mutually exclusive.
i) Avilaterone may contain amorphous abiraterone;
ia) Abiraterone may contain less than 5% crystalline material, may contain less than 1% crystalline material, and may not contain crystalline material;
ii) Abiraterone may contain at least 99% abiraterone;
iii) Aviraterone has the following structural formula:

May contain at least 99% abiraterone;
iv) Abiraterone may contain at least 99% abiraterone salt;
v) Abiraterone may contain at least 99% abiraterone ester;
va) Avilaterone ester has the following structural formula:

May contain abiraterone acetate;
vi) Abiraterone may contain at least 99% abiraterone solvate;
vii) Abiraterone may contain at least 99% abiraterone hydrate;
viii) The pharmaceutical product may contain 10 mg, 25 mg, 50 mg, 70 mg, 100 mg, or 250 mg of amorphous avilateron;
ix) The pharmaceutical product has the same or greater therapeutic effect, bioavailability, C _min as or greater than 50 mg, 70 mg, 100 mg, 250 mg, 500 mg, or 1000 mg of crystalline abiraterone or crystalline abiraterone acetate when ingested on an empty stomach. , C _max , or T _max may be contained in sufficient amounts of amorphous abiraterone or a salt thereof in the patient;
x) The pharmaceutical product may contain an amount of amorphous avilateron or a salt thereof in an amount of 10 mg, 25 mg, 50 mg, 70 mg, 100 mg, 250 mg, or 500 mg;
xi) The pharmaceutical product has the same or greater therapeutic effect and bioavailability as 10 mg, 25 mg, 50 mg, 70 mg, 100 mg, 250 mg, 500 mg or 1000 mg of crystalline abiraterone or crystalline abiraterone acetate when taken on an empty stomach. , C _min , C _max , or T _max may be contained in sufficient amounts of amorphous abiraterone or a salt thereof in the patient;
xii) The pharmaceutical formulation may contain 1,000 mg of amorphous avilateron or a salt thereof;
xiii) The pharmaceutical product has the same or greater therapeutic effect, bioavailability, C _min , C _max , or T _max in patients with 1,000 mg of crystalline abiraterone or crystalline abiraterone acetate when ingested on an empty stomach. It may contain a sufficient amount of amorphous abiraterone or a salt thereof to realize it;
xiv) Abiraterone or a salt thereof and a cyclic oligomer may be present in a molar ratio of 1: 0.25 to 1:25;
xv) Abiraterone or a salt thereof and a cyclic oligomer may be present in a molar ratio of at least 1: 2;
xvi) The pharmaceutical product may contain 1% by weight to 50% by weight of amorphous avilateron or a salt thereof;
xvii) The pharmaceutical formulation may contain at least 10% by weight amorphous avilateron or a salt thereof;
xviii) Cyclic oligomer excipients may include cyclic oligosaccharides or cyclic oligosaccharide derivatives;
xvii-a) Cyclic oligosaccharides or cyclic oligosaccharide derivatives may include cyclodextrins or cyclodextrin derivatives;
xvii-aa) Cyclodextrin derivative may contain hydroxypropyl β cyclodextrin;
xvii-ab) Cyclodextrin derivatives may include sodium (Na) sulfo-butyl ether β cyclodextrin;
xvii-ac) Cyclodextrin derivatives may contain hydroxypropyl groups;
xvii-ad) Cyclodextrin derivatives may contain sulfo-butyl ether functional groups;
xvii-ae) Cyclodextrin derivatives may contain a methyl group;
xvii-af) Cyclodextrin derivatives may contain carboxymethyl groups;
xix) The pharmaceutical formulation may contain 50% by weight to 99% by weight of the cyclic oligomeric excipient;
xx) The pharmaceutical formulation may contain at least 90% by weight cyclic oligomer excipient;
xxi) The pharmaceutical formulation may contain additional excipients;
xxi-a) Cyclic oligomeric excipient may be a primary excipient;
xxi-b) Additional excipients may be primary excipients;
xxi-ba) Additional excipients may be secondary excipients;
xxi-c) Additional excipients may be polymer excipients;
xxi-ca) Polymer excipients may be water soluble;
xxi-cb) Polymer excipients may include nonionic polymers;
xxi-cc) Polymer excipients may include ionic polymers;
xxi-cd) Polymer excipients may include hydroxypropylmethylcellulose acetate succinate;
xxi-cda) Hydroxypropylmethylcellulose acetate succinate may have 5-14% acetate substitution and 4-18% succinate substitution;
xxi-cdaa) Hydroxypropylmethylcellulose acetate succinate may have 10-14% acetate substitution and 4-8% succinate substitution;
xxi-cdaaa) Hydroxypropylmethylcellulose acetate succinate may have 12% acetate substitution and 6% succinate substitution;
xxi-d) The pharmaceutical formulation may contain 1% to 49% by weight of additional excipients;
xxi-e) The pharmaceutical formulation may contain up to 10% by weight of additional excipients;
xxii) The pharmaceutical formulation may include a glucocorticoid replacement API;
xxii-a) The glucocorticoid replacement API may include prednisone, methylprednisolone, prednisolone, methylprednisolone, dexamethasone, or a combination thereof;
xxiii) The pharmaceutical product is an amorphous abiraterone or a salt thereof in an amount sufficient to achieve a C _max increase of at least 6 times in the patient with an equal amount of crystalline abiraterone or crystalline abiraterone acetate when ingested on an empty stomach. May include;
xxiv) The pharmaceutical product is an amorphous abiraterone or an amorphous abiraterone in an amount sufficient to achieve an AUC _0-t increase of at least 3-fold compared to an equal amount of crystalline abiraterone or crystalline abiraterone acetate when ingested on an empty stomach. May contain that salt;
xxv) The pharmaceutical product is an amorphous abiraterone or an amorphous abiraterone in an amount sufficient to achieve a C _max variation reduction of at least 6% of an equal amount of crystalline abiraterone or crystalline abiraterone acetate when ingested on an empty stomach in a patient. It may contain salt.
xxvi) The pharmaceutical product is an amorphous abiraterone in an amount sufficient to achieve an AUC _0-t variation reduction of at least 4% of an equal amount of crystalline abiraterone or crystalline abiraterone acetate when ingested on an empty stomach. Alternatively, the salt may be contained.
xxvii) The pharmaceutical product provides an equal amount of C _max variation reduction of at least 25% of crystalline avilateron or crystalline avilatelate acetate when ingested on an empty stomach in patients when ingested in a fed state. May contain a sufficient amount of amorphous avilateron or a salt thereof.
xxviii) The pharmaceutical product achieves an AUC _0-t variation reduction of at least 23% of the same amount of crystalline avilateron or crystalline avilateron acetate when ingested on an empty stomach in patients when ingested in a fed state. It may contain a sufficient amount of amorphous avilateron or a salt thereof;
xxix) The pharmaceutical product is an amorphous avirateron or its sufficient amount to achieve a Cmax variation of less than 30% when ingested in a fasted state compared to the Cmax when ingested in a fasted state. May contain salt;
xxx) The pharmaceutical product is sufficient to achieve an AUC _0-t variation of less than 10% in patients when ingested in a fasted state compared to AUC _0-t when ingested in a fasted state. May contain an amount of amorphous avilateron or a salt thereof;
xxxi) The pharmaceutical product is sufficient to achieve an average C _min of at least 35 ng / mL in the human patient population when administered once, twice daily, three times daily, or four times daily. It may contain an amount of amorphous avilateron or a salt thereof.
xxxii) Pharmaceutical formulations have increased therapeutic efficacy and bioavailability compared to equal or higher amounts of crystalline abiraterone or equal or higher amounts of crystalline abiraterone acetate when ingested in a fasted state. , Cmin, or Cmax may contain an amount of amorphous abiraterone or a salt thereof sufficient to achieve in patients with metastatic castration-resistant prostate cancer and primary resistance;
xxxiii) Pharmaceutical formulations have increased therapeutic efficacy and bioavailability compared to equal or higher amounts of crystalline abiraterone or equal or higher amounts of crystalline abiraterone acetate when ingested in a fasted state. , Cmin, or Cmax may contain an amount of amorphous abiraterone or a salt thereof sufficient to achieve in patients with metastatic castration-resistant prostate cancer and acquired resistance;
xxxiv) Pharmaceutical formulations have increased therapeutic efficacy and bioavailability compared to equal or higher amounts of crystalline abiraterone or equal or higher amounts of crystalline abiraterone acetate when ingested in a fasted state. , Cmin, or Cmax may contain an amount of amorphous abiraterone or a salt thereof sufficient to achieve in patients with triple negative breast cancer;
xxxv) Pharmaceutical formulations have increased therapeutic efficacy and bioavailability compared to equal or higher amounts of crystalline abiraterone or equal or higher amounts of crystalline abiraterone acetate when ingested in a fasted state. , Cmin, or Cmax may contain an amount of amorphous abiraterone or a salt thereof sufficient to achieve in patients with non-metastatic castration-resistant prostate cancer.
xxxvi) The pharmaceutical preparation may contain an inclusion complex containing an amorphous avilateron and a cyclic oligomer excipient.
xxxvi-a) The pharmaceutical preparation containing the inclusion complex may contain up to 30% by weight, 20% by weight, or 10% by weight of amorphous avilateron.
xxxvi-b) The pharmaceutical preparation containing the inclusion complex may contain up to 10% by weight of amorphous avilateron.
xxxvi-c) The pharmaceutical preparation containing the inclusion complex may be formed by a method including thermokinetic compounding.
xxxvi-d) At least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 99.9% of amorphous avilateron is present in the inclusion complex. May be good.
xxxvi-e) Less than 10%, less than 9%, 8% of avilateron in response to heating the pharmaceutical formulation to a temperature up to 90% of the melting point of crystalline avilateron and cooling the pharmaceutical formulation to room temperature. Less than, less than 7%, less than 6%, less than 5%, less than 4%, less than 3%, less than 2%, less than 1%, or less than 0.1% may be crystalline.
xxxvi-ei) Less than 10%, less than 9%, less than 8%, less than 7%, less than 6%, less than 5%, less than 4%, less than 3%, less than 2%, less than 1% of crystalline abiraterone Alternatively, less than 0.1% may be confirmed by methods involving X-ray diffraction.
xxxvi-f) Pharmaceutical formulations containing inclusion complex include 0.01N HCl, as well as Simulated Gastric Fluid (SGF), Fasted State Simulated Intestinal Fluid (FaSSIF), and Simulated Feeding. When demonstrated by elution in at least one of the bio-related mediums selected from Fed State Simulated Intestinal Fluid (FeSSIF), it is more than a pharmaceutical formulation containing neat crystalline avilateron. , May have at least 13-17-fold increased elution in the patient's gastrointestinal tract.
xxxvi-g) Pharmaceutical formulations containing inclusion complexes increase the bioavailability of abiraterone in patients by up to 4-fold compared to higher amounts of crystalline abiraterone or crystalline abiraterone acetate when ingested on an empty stomach. May have.

The present disclosure further provides tablets for oral administration, which may include any pharmaceutical formulation described above or elsewhere herein.

According to various further aspects of the tablets, all of which can be combined with each other, unless they are clearly mutually exclusive.
i) Tablets may contain a coating;
ia) The coating may include a glucocorticoid supplement API;
iaa) The glucocorticoid replacement API may include prednisone, methylprednisolone, prednisolone, methylprednisolone, dexamethasone, or a combination thereof;
ii) Tablets may contain an external phase containing an additional amount of cyclic oligomeric excipient;
iii) The tablet may contain an external phase containing at least one additional excipient;
iv) Tablets may contain increasing concentration polymers;
iv-a) The increasing concentration polymer may contain hydroxypropylmethylcellulose acetate succinate.
v) The tablet may contain an external phase containing one or more water expandable polymers.
va) The water-expandable polymer may include polyethylene oxide, hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, and carboxymethyl cellulose.
vb) The tablet may be a tablet shaped such that the size and shape of the tablet prevent the tablet from passing through the pylorus of the stomach when the water-swellable polymer is hydrated.
vc) Tablets have a drug release profile, eg, immediate release, or modified release, eg, extended release, which may be sustained or sustained release, or pulsatile or delayed release. You may.

Tablets may contain an external phase containing at least one additional drug release modifying excipient, or may contain an external phase containing one or more hydrogel forming excipients, of polyethylene oxide and hydroxypropylmethylcellulose. It may include an external phase containing a combination.

The present disclosure also combines crystalline avilateron or a salt thereof and a cyclic oligomer excipient in a thermokinetic mixer at a temperature equal to or less than 200 ° C for less than 300 seconds to form an amorphous avirateron. Also provided is a method of forming a pharmaceutical formulation by forming a cyclic oligomeric excipient.

According to various further aspects of the method, all may be combined with each other, unless they are clearly mutually exclusive.
i) The pharmaceutical product may be any pharmaceutical product described above or elsewhere herein;
ii) The method may also include the step of blending at least one additional excipient with crystalline abiraterone and cyclic oligomeric excipients;
iii) Formulation in a thermodynamic mixer may not cause substantial pyrolysis of abiraterone or its salts;
iv) Formulation in a thermodynamic mixer may not cause substantial thermal decomposition of cyclic oligomeric excipients;
v) Formulation in a thermodynamic mixer may not cause substantial pyrolysis of additional excipients.

The present disclosure is also a method of forming a pharmaceutical preparation by a hot melt extrusion in which a crystalline avilateron or a salt thereof and a cyclic oligomer excipient are treated to form an amorphous avilateron and a cyclic oligomer excipient. Melt extrusion also provides a method in which the amorphous material is substantially free of thermal decomposition.

According to various further aspects of the method, all may be combined with each other, unless they are clearly mutually exclusive.
i) The pharmaceutical product may be any pharmaceutical product described above or elsewhere herein;
ii) The method may also include treating at least one additional excipient with crystalline abiraterone and cyclic oligomeric excipients;
iii) Melt treatment may not cause substantial thermal decomposition of cyclic oligomeric excipients;
iv) Melt treatment may not cause substantial thermal decomposition of additional excipients.

The present disclosure describes a step of dissolving crystalline avilateron or a salt thereof and a cyclic oligomer excipient in a common organic solvent to form a dissolved mixture, and spray-drying the dissolved mixture to obtain an amorphous avilateron and a cyclic oligomer excipient. Further provided is a method of forming a pharmaceutical formulation, including the step of forming.

According to various further aspects of the method, all may be combined with each other, unless they are clearly mutually exclusive.
i) The pharmaceutical product may be any pharmaceutical product described above or elsewhere herein;
ii) The method may further include dissolving at least one additional excipient with crystalline abiraterone and cyclic oligomeric excipient, as well as spray drying;
iii) Spray drying may not cause substantial pyrolysis of abiraterone;
iv) Spray drying may not cause substantial thermal decomposition of cyclic oligomer excipients;
v) Spray drying may not cause substantial pyrolysis of additional excipients.

The present disclosure also comprises avilateron and cyclic oligomers by methods comprising wet mass extrusion, high intensity mixing, high intensity mixing with solvent, ball milling, or ball milling with solvent. Also included is a method of forming a pharmaceutical formulation comprising the step of combining the excipients to form a cyclic oligomer with amorphous avilateron.

The present disclosure is also any pharmaceutical formulation prepared according to any of the methods described above, which may have any of the other features of the pharmaceutical formulation described above or elsewhere herein. Also includes.

The present disclosure is also any pharmaceutical product prepared according to any of the methods described above, which may have any of the pharmaceutical formulations or other features of the tablet described above or elsewhere herein. It also includes tablets containing a specific formulation.

The present disclosure also has prostate cancer with any pharmaceutical formulation described above or elsewhere herein or any tablet described above or elsewhere herein. It also provides a method of treating prostate cancer in a patient by administration to the patient.

According to various further aspects of the method, all may be combined with each other, unless they are clearly mutually exclusive.
i) Patients may have castration-resistant prostate cancer, metastatic cast-resistant prostate cancer, metastatic prostate cancer, locally advanced prostate cancer, recurrent prostate cancer, non-metastatic cast-resistant prostate cancer, or other high-risk prostate cancer. May have cancer;
ii) The patient may have previously been treated with chemotherapy;
ii-a) Chemotherapy may include docetaxel;
iii) The patient may have previously been treated with enzalutamide;
iv) Patients may have previously experienced a suboptimal response to crystalline abiraterone acetate;
v) The pharmaceutical product or tablet may be administered to the patient in combination with androgen deprivation therapy;
vi) The pharmaceutical product or tablet may be administered to the patient in combination with the glucocorticoid replacement API;
vii) Pharmaceutical product or tablet may be administered once daily;
viii) The pharmaceutical product or tablet may be administered twice daily, three times daily, four times daily, or more;
ix) The pharmaceutical product or tablet may contain amorphous abiraterone or a salt thereof, which is sufficient for achieving the same or higher therapeutic effect, bioavailability, C _min , C _max , or T _max . It may be administered in a weight unit dose of abiraterone, which is smaller than the weight unit dose.
x) Patients may have metastatic castration-resistant prostate cancer and primary resistance to treatment with crystalline abiraterone or crystalline abiraterone acetate;
xi) Patients may have metastatic castration-resistant prostate cancer and acquired resistance to treatment with crystalline abiraterone or crystalline abiraterone acetate.

The present disclosure also includes any pharmaceutical formulation described above or elsewhere herein, or any tablet described above or elsewhere herein, for androgen-sensitive cancer. Also provided are methods of treating various androgen-sensitive cancers by administration to patients with.

According to various further aspects of the method, all may be combined with each other, unless they are clearly mutually exclusive.
i. Patients may have breast cancer or triple negative androgen receptor positive locally advanced / metastatic breast cancer or ER positive HER2-negative or ER positive metastatic breast cancer or apocrine breast cancer;
ii. Patients may have Cushing's syndrome and adrenocortical carcinoma;
iii. Patients may have urothelial cancer or bladder cancer or bladder tumor;
iv. Patients may have relapsed / metastatic salivary gland cancers that express androgen receptors, or relapsed and / or metastatic salivary gland cancers or salivary gland tumors or salivary gland tumors;
v. Patients may have previously been treated with chemotherapy;
iv-a) Chemotherapy may include docetaxel;
vi. Patients may have previously been treated with medications used for breast cancer, adrenal cancer, and salivary gland cancer;
vii. Patients may have previously experienced a suboptimal response to crystalline abiraterone acetate;
viii. Pharmaceutical formulations or tablets may be administered to patients in combination with androgen deprivation therapy;
ix. The pharmaceutical product or tablet may be administered to the patient in combination with the glucocorticoid replacement API;
x. The pharmaceutical product or tablet may be administered once daily;
xi. The pharmaceutical product or tablet may be administered twice daily, three times daily, four times daily, or more;
xii. Pharmaceutical formulations or tablets may contain amorphous abiraterone, in weight units of abiraterone acetate sufficient to achieve equivalent or higher therapeutic effect, bioavailability, C _min , C _max , or T _max . It may be administered at a dose in weight units of abiraterone, which is smaller than the dose of.

It is intended that any method or composition described herein can be performed in connection with any other method or composition described herein.

Any aspect discussed herein can be performed in connection with any method or composition of the invention, and vice versa. In addition, the compositions and kits of the invention can be used to realize the methods of the invention.

Throughout this application, the term "about" is used to indicate that a value includes an inherent variation in the device, method error, or variation that exists between test subjects. Be done.

There is only one term such as "one (a)", "one (an)", and "the" unless it is specifically stated that one entity is intended. Includes a general class of entities that are not intended to refer to an entity and for which examples are given for illustration purposes.

Moreover, unless it is made clear that an exact value is intended, the numbers described herein will vary above or below, or "almost" the same, as the numbers may achieve substantially the same results. It must be interpreted to include fluctuations in numbers.

Finally, the derivatives of the present disclosure may include chemically modified molecules with the addition, removal, or substitution of chemical moieties in the parent molecule.

The present disclosure may be further understood by reference to the accompanying drawings in combination with the detailed description below.

It is an exemplary X-ray diffraction pattern of pure crystalline abiraterone. It is an exemplary X-ray diffraction pattern of a set of abiraterone solid dispersions containing various polymeric excipients. Excipient types (cellulose-based, polyvinyl-based, or acrylate-based) are shown. See the description in Figure 2-1. It is an exemplary X-ray diffraction pattern of the amorphous solid dispersion of abiraterone and hydroxypropyl β cyclodextrin. FIG. 6 is a graph reporting an exemplary dissolved avilateron concentration vs. time (elution profile) for various solid dispersions of pure crystalline avilateron, or avilateron and polymer excipients or hydroxypropyl β cyclodextrin excipients. FIG. 6 is a graph reporting exemplary dissolved avilateron concentration vs. time (elution profile) for amorphous solid dispersion of avilateron and hydroxypropyl β cyclodextrin primary excipients in the presence of various polymer secondary excipients. Only the neutral phase elution profile was shown. Hydroxypropylmethylcellulose acetates with 10-14% acetate substitutions and 4-8% succinate substitutions with avilateron and various amounts of hydroxypropyl β-cyclodextrin primary excipients and secondary excipients. It is an exemplary X-ray diffraction pattern of a set of amorphous solid dispersions of cusinate. Abilateron, various amounts of hydroxypropyl β-cyclodextrin primary excipient, and various amounts of secondary excipient, hydroxypropylmethylcellulose acetate with 10-14% acetate substitution and 4-8% succinate substitution. It is a set of graphs reporting an exemplary dissolved avilateron concentration vs. time (elution profile) in an acidic phase for an amorphous solid dispersion of succinate. Abilateron, various amounts of hydroxypropyl β-cyclodextrin primary excipient, and various amounts of secondary excipient, hydroxypropylmethylcellulose acetate with 10-14% acetate substitution and 4-8% succinate substitution. It is a set of graphs reporting an exemplary dissolved avilateron concentration vs. time (elution profile) in a neutral phase for an amorphous solid dispersion of succinate. Avilateron and hydroxypropylmethylcellulose acetate succinates with polymer excipients or hydroxypropyl β cyclodextrin primary excipients and secondary excipients 10-14% acetate substitution and 4-8% succinate substitution. FIG. 6 is a graph reporting an exemplary dissolution avilateron concentration vs. time (elution profile) as a function of the amount of drug charged in the dissolution vessel (25-200 times the intrinsic solubility) for amorphous solid dispersion. .. Illustrative X-rays of the amorphous solid dispersion of avilateron and hydroxypropyl β-cyclodextrin in 1: 4 (Example 7.1) and 3: 7 (Example 7.2) weight ratios formed by thermokinetic processing. It is a diffraction diagram. Solid dispersion of avilateron and hydroxypropyl β-cyclodextrin in weight ratios of 1: 9 (Example 2.4), 1: 4 (Example 7.1), and 3: 7 (Example 7.2) formed by thermodynamic formulation. It is a graph which reported the example dissolution avilateron concentration vs. time (elution profile) with respect to. It is an exemplary X-ray diffraction pattern of pure crystalline abiraterone acetate. It is an exemplary X-ray diffraction pattern of a set of solid dispersions of abiraterone acetate containing various polymeric excipients. Excipient types (cellulose-based, polyvinyl-based, or acrylate-based) are shown. See the description in Figure 12-1. It is a graph which reported the concentration | time (elution profile) of an exemplary dissolved abiraterone acetate for various solid dispersions of pure crystalline abiraterone acetate, or abiraterone acetate and polymer excipients. It is an exemplary X-ray diffraction pattern of the amorphous solid dispersion of abiraterone acetate and hydroxypropyl β cyclodextrin. It is a graph which reported the concentration | time (elution profile) of the pure crystalline avilateron acetate, and the exemplary dissolved avilatelon acetate for the amorphous solid dispersion of avilateron acetate and hydroxypropyl β cyclodextrin. It is an exemplary X-ray diffraction pattern of an amorphous solid dispersion of avilateron acetate and hydroxypropyl β cyclodextrin in a 1: 4 (Example 10.1) weight ratio formed by thermodynamic compounding. An exemplary dissolved abiraterone acetate concentration vs. time (elution profile) for solid dispersion of abiraterone acetate and hydroxypropyl β cyclodextrin in weight ratios of 1: 9 (Example 9.1) and 1: 4 (Example 10.1) is reported. It is a graph. Avilaterone Acetate-Hydroxypropyl β Cyclodextrin (1: 9w / w) An exemplary dissolved abiraterone acetate concentration as a function of the amount of drug (100-400 times the intrinsic solubility) filled in the elution vessel in the form of ASD. It is a graph which reported the time (dissolution profile). It is a graph which reported the exemplary abiraterone concentration vs. time from the dissolution test of the 50 mg tablet prepared according to Example 10 in 900 ml of 0.01N HCl. Exemplary abiraterone plasma after oral administration of abiraterone IR prepared according to Example 11.1 and XR tablets (50 mg abiraterone) prepared according to Example 11.2 to male beagle dogs compared to the reference Zytiga (250 mg abiraterone acetate). It is a graph which reported the concentration vs. time profile. FIG. 6 is a graph reporting an exemplary total oral abiraterone exposure (AUC) vs. dose curve from an incremental dose PK study in SCID mice comparing the composition prepared according to Example 2.4 with abiraterone acetate. It is a graph reporting an exemplary tumor growth curve after once-daily administration of abiraterone acetate or the composition from Example 2.4 to 22RV1 xenograft mice at two dose levels. 200 mg DST-2970 IR, fasting; 200 mg DST-2970 IR, feeding; or 1,000 mg ZYTIGA®, exemplary geometric mean plasma abiraterone levels in healthy male subjects after treatment in fasted state ( It is a graph which reported ng / mL). 200 mg DST-2970 IR, fasting; 200 mg DST-2970 IR, feeding; or 1,000 mg ZYTIGA®, exemplary arithmetic mean plasma abiraterone levels in healthy male subjects after treatment in the fasted state ( It is a graph which reported ng / mL). 200 mg DST-2970 IR, a graph reporting exemplary individual patient data for plasma abilateron levels (ng / mL) in healthy male subjects after treatment in a fasting state. 200 mg DST-2970 IR, a graph reporting exemplary individual patient data of plasma abilateron levels (ng / mL) in healthy male subjects after treatment in a feeding state. 1,000 mg ZYTIGA®, a graph reporting exemplary individual patient data for plasma abiraterone levels (ng / mL) in healthy male subjects after treatment in a fasting state. (Top panel) Pure abiraterone API, melt quenched abiraterone API, and HPBCD; (Bottom panel) Lot 1 PM and Lots 1-5 KinetiSol® Solid Dispersions KSD (DisperSol Technologies LLC, Texas) A set of example X-ray diffraction diagrams (dotted circles in the upper figure indicate characteristic peaks of the abiraterone API, and dotted lines in the lower figure indicate the peak position regions of these characteristic peaks. Shows). Examples of lot 1 PM and lots 1-5 KSD mDSC thermograms. Example ¹³ C ss NMR spectra of pure abiraterone API, HPBCD, lot 1 PM, and lots 1-5 KSD (dotted rectangles are sp ³ mixed carbon atoms, C 3 carbon atoms, and sp ² mixed carbon atoms of pure abiraterone API. Indicates the area of the atom). Example 2 D ¹³ C- ¹ H HETCOR spectra of pure abiraterone API (black), HPBCD (red), and lot 3 KSD (blue). A ¹ H cross sestion at 103.9 ppm in ¹³ C dimensions (dimention) is shown in 2D spectra. It is a graph which reported the example phase solubility profile of abiraterone-HPBCD in 0.01N HCl and FaSSIF. It is a graph which reported the X-ray diffraction pattern of lot 1-3 KSD at 90 ℃ and 150 ℃. (The dotted line indicates the peak position region of the characteristic pee of abiraterone). Examples of pure abiraterone API and lots 1-5 KSD are graphs reporting in vitro, non-sink, gastric transfer elution profiles. Red region (0.01N HCl) and blue region (FaSSIF). FIG. 6 is a graph reporting an example in vivo mean plasma concentration v / s time profile from oral dosing of Zytiga® and lots 1-3 tablets in fasting non-naive male beagle dogs. It is a graph which reported the in vitro percent relative performance and the in vivo percent relative performance of examples of KSD with various drug loading amounts. Cyclodextrin host molecule and API of an inclusion complex with one host molecule and one guest molecule (left panel), or two host molecules and one guest molecule (right panel) It is a schematic diagram which showed the Example of a guest molecule. It shows the molecular structure of β-cyclodextrin with varying degrees of substitution at positions 2, 3, and 6. In the formula, R = CH ₂ CHOHCH ₃ or H.

Detailed Description The present disclosure relates to abiraterone pharmaceutical formulations and methods of forming and administering such pharmaceutical formulations.

A. Pharmaceutical product The pharmaceutical product of the present disclosure may contain abiraterone as an active ingredient (API). Abiraterone includes both active and modified forms of abiraterone, either in the amorphous or crystalline state, unless otherwise specified herein. Modified forms of abiraterone include its pharmaceutically acceptable salts, esters, derivatives, analogs, prodrugs, hydrates, or solvate compounds. In certain embodiments, the term abiraterone excludes abiraterone prodrugs such as abiraterone acetate.

を有する。 The abiraterone is (3β) -17- (3-pyridinyl) androsta-5,6-diene-3-ol, and the formula:

Have.

を有する。 Abiraterone acetate, such as ZYTIGA®, is an ester of abiraterone, (3β) -17- (3-pyridinyl) androsta-5,16-diene-3-all acetate, formula:

Have.

The pharmaceutical product may contain abiraterone, which is known to be resistant to a pharmaceutical product having sufficient bioavailability or therapeutic effect prior to the present disclosure. In particular, as long as the pharmaceutical formulations of the present disclosure contain both abiraterone and its variants, eg, pharmaceutically acceptable salts, esters, derivatives, analogs, prodrugs, hydrates, or solvates thereof. It may contain at least 80%, at least 95%, at least 99%, or at least 99% abiraterone in molecular percent, by weight, or by volume as compared to whole abiraterone and modified abiraterone.

The abiraterone in the pharmaceutical formulations of the present disclosure may be free of significant impurities. For example, abiraterone includes the U.S. Department of Health and Human Services, Food and Drug Administration, which is incorporated herein by reference or at a level above the thresholds that have been qualified by toxicological studies. (Food and Drug Administration), Center for Drug Evaluation and Research (CDER), Center for Biologics Evaluation and Research, published in July 2006, Guidance for Industry, Q3B (R2) Impurities in New Drug Products (As specified in the International Committee for Harmonization, there may be no impurities at levels above the acceptable threshold for unknown impurities, or in the pharmaceutical formulations of this disclosure. Avilaterone is less than 1.0% by weight, less than 0.75% by weight, less than 0.5% by weight, less than 0.1% by weight, 0.05% by weight compared to the total weight of abiraterone and impurities compared to standard substances with known concentrations in mg / mL. May have less than or less than 0.01% by weight of impurities. Alternatively, the abiraterone in the pharmaceutical formulations of the present disclosure is at least 90 compared to the unblended abiraterone as measured by HPLC. May retain%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 99.9% drug activity or efficacy. Aliases are abiraterone degradation products. For example, the pharmaceutical formulation of the present disclosure comprising abiraterone may further comprise a glucocorticoid supplement API. A suitable glucocorticoid supplement API may include a moderate biological halving. It may have a period, eg, 18-36 hours, or a long biological half-life, eg, 36-54 hours. Suitable glucocorticoid APIs include dexamethasone, prednison or prednisolone, or alkylated forms, eg. , Methylprednison and methylprednisolone, and any combination thereof. Other glucocorticoid supplement APIs are also used. In some cases.

The glucocorticoid supplement API in the pharmaceutical formulations of the present disclosure may also be free of significant levels of impurities. For example, for glucocorticoid supplementation, the US Department of Health and Social Welfare, Food and Drug Administration, Drug Evaluation and Research Center (CDER), at levels above the thresholds that have been qualified by toxicological studies, or incorporated herein by reference. ), The acceptable threshold for unknown impurities as specified in the Guidance for Industry, Q3B (R2) Impurities in New Drug Products (International Committee for Harmonization), published in July 2006 by the Biopharmaceutical Evaluation and Research Center. Impurities may be absent at levels above, or the glucocorticoid supplement API in the pharmaceutical formulations of the present disclosure is the glucocorticoid supplement API and the total weight of the impurities compared to the standard substance at known concentrations in mg / mL units. May have impurities less than 1.0% by weight, less than 0.75% by weight, less than 0.5% by weight, less than 0.1% by weight, less than 0.05% by weight, or less than 0.01% by weight. The glucocorticoid supplement API in the pharmaceutical formulation, when measured by HPLC, is at least 90%, 91%, 92%, 93%, 94%, 95%, compared to the glucocorticoid supplement API that was not formulated. It may retain 96%, 97%, 98%, 99%, or 99.9% drug activity or efficacy. Impurities may include glucocorticoid supplement API degradation products, such as thermal degradation products.

The pharmaceutical formulations of the present disclosure may further comprise one or more other APIs in addition to the abiraterone. Suitable additional APIs include prostate cancer, or other APIs approved to treat prostate cancer or the side effects of prostate cancer treatment. These additional APIs may be active. These APIs may not be previously formulated, may not be formulated with an orally administrable pharmaceutical formulation, may not be formulated with abiraterone, or may not be formulated in the active form. Suitable additional APIs include those used in androgen ablation therapy, non-steroidal androgen receptor inhibitors, taxans, gonad stimulating hormone-releasing hormone antagonists, gonad stimulating hormone-releasing hormone analogs, androgen receptor antagonists, non-steroidal anti-steroids. Includes androgens, analogs of luteinizing hormone-releasing hormones, anthracenedione antibiotics, and radiopharmaceuticals, and any combination thereof. These suitable additional APIs include appartamides such as ERLEADA ™ (Janssen), bicalutamides such as CASODEX® (AstraZeneca, North Carolina, US), Kabazitaxel such as JEVTANA® (Sanofi). -Aventis, France), degalerix, docetaxel, eg TAXOTERE® (Sanofi-Aventis), enzalutamide, eg XTANDI® (Astellas Pharma, Japan), flutamid, goserelin acetate, eg ZOLADEX®. ) (TerSera Therapeutics, Iowa, US), lyuprolide acetate, eg LUPRON® (Abbvie, Illinois, US), LUPRON® DEPOT (Abbvie), LUPRON® DEPOT-PED (Abbvie), And VIADUR® (ALZA Corporation, California, US), mitoxanthron hydrochloride, nitamide, eg NILANDRON® (Concordia Pharmaceuticals, Barbados), and radium dichloride 223, eg, XOFIGO® (registered trademark). Bayer Healthcare Pharmaceuticals, New Jersey, US), as well as any combination thereof.

Any additional APIs in the pharmaceutical formulations of the present disclosure may not contain significant levels of impurities. For example, additional APIs are incorporated herein by reference or at levels above the thresholds that have been qualified by toxicology testing, US Department of Health and Social Welfare, Food and Drug Administration, Drug Evaluation and Research Center (CDER), Levels above the acceptable threshold for unknown impurities as specified in the Guidance for Industry, Q3B (R2) Impurities in New Drug Products (International Committee for Harmonization), published by the Center for Biologics Evaluation and Research in July 2006. May be free of impurities, or the additional APIs in the pharmaceutical formulations of the present disclosure are compared to the standard substance at known concentrations in mg / mL units, compared to the additional APIs and the total weight of the impurities. May have impurities less than 1.0% by weight, less than 0.75% by weight, less than 0.5% by weight, less than 0.1% by weight, less than 0.05% by weight, or less than 0.01% by weight. Alternatively, the pharmaceutical formulations of the present disclosure. The additional APIs inside are at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, when measured by HPLC, compared to the additional APIs that were not formulated. It may retain 98%, 99%, or 99.9% drug activity or efficacy. Impurities may include additional API degradation products, such as thermal degradation products.

The pharmaceutical formulations of the present disclosure further comprise at least one excipient. When multiple excipients are used in the pharmaceutical formulations of the present disclosure, the excipient present in the highest amount by weight percent is typically referred to as the primary excipient, while the other excipients are by weight. It is called a secondary excipient, a tertiary excipient, etc. in order from the one with the largest amount in percentage.

The pharmaceutical formulations of the present disclosure include cyclic oligomer excipients such as cyclic oligosaccharides or cyclic oligosaccharide derivative excipients, cyclic peptide oligomers or cyclic peptide oligomer derivatives, cyclic polycarbonate oligomers or cyclic polycarbonate oligomer derivatives, and any thereof. May include more combinations of. Oligosaccharide excipients may have 3 to 15 sugar monomer units, such as glucose units and glucose derivative units, fructose units and fructose derivative units, galactose and galactose derivative units, and any combination thereof. .. The sugar monomer unit may be derivatized with a functional group, for example, a sulfobutyl ether, a hydroxypropyl derivative, or a carboxymethyl derivative, or may be derivatized by methylation.

For example, the pharmaceutical formulations of the present disclosure may include cyclodextrin (CD).

Cyclodextrin (CD) is a cyclic oligomer containing at least 6 D- (+)-glucopyranose units bound by an α (1 → 4) glycosidic bond (Davis, Mark E., and Marcus E. Brewster). 2004.'Cyclodextrin-based pharmaceutics: past, present and future', Nature Reviews Drug Discovery, 3: 1023-35; Loftsson, T., P. Jarho, M. Masson, and T. Jarvinen. 2005.'Cyclodextrins in drug delivery', Expert Opin Drug Deliv, 2: 335-51.). The glucopyranose unit on the CD exists in a chair-shaped constellation, which causes the CD to have a truncated cone-like or toroidal structure (Loftsson, T., P. Jarho, M. Masson, and T. Jarvinen. 2005.'Cyclodextrins in drug delivery', Expert Opin Drug Deliv, 2: 335-51.). The outer surface of the CD has a secondary hydroxy group extending from the wide end of the cone and a primary group extending from the narrow end, which imparts hydrophilicity to the outer surface ( Sharma, Neha, and Ashish Baldi. 2016.'Exploring versatile applications of cyclodextrins: an overview', Drug Delivery, 23: 729-47.). The internal cavities of the CD contain skeletal carbon with hydrogen atoms and oxygen crosslinks, which imparts lipophilicity to the internal cavities (Sharma, Neha, and Ashish Baldi. 2016.'Exploring versatile applications of cyclodextrins: an overview' , Drug Delivery, 23: 729-47.).

Accordingly, in some embodiments, the present disclosure comprises a pharmaceutical formulation comprising avirateron and a cyclic oligomer, such as cyclodextrin, or an inclusion complex of other cyclic oligomers described herein, and such pharmaceuticals. A method for forming a pharmaceutical product is provided. The inclusion complex in the pharmaceutical formulation of the present disclosure differs from the amorphous solid dispersion in which the avilateron is dispersed between the excipient molecules. The inclusion complex in the pharmaceutical formulation of the present disclosure comprises an amorphous avilateron contained within a cyclic oligomer molecular structure. In particular, in some embodiments, the inclusion complex in the pharmaceutical formulation of the present disclosure may be formed using a process comprising a thermodynamic formulation of abiraterone and a cyclic oligomer. As described herein, in some embodiments, the properties of the inclusion complex of abiraterone and the cyclic oligomer depend on the molar ratio of the abiraterone to the cyclic oligomer and the properties of the abiraterone to the cyclic oligomer. The inclusion complex in the pharmaceutical formulations of the present disclosure is for administration to a patient for the purpose of increasing the solubility, bioavailability, or both of abiraterone and correspondingly treating a condition responsive to abiraterone. May improve drug properties. Furthermore, it is surprising that abiraterone-containing inclusion complexes are formed using the thermodynamic compounding process described herein by high shear mixing in the solid state without the use of solvents or external heat. And it was unexpected.

For example, in some embodiments, the cyclic oligomer, eg, CD, or other cyclic oligomer described herein, is an abiraterone or a portion of the abiraterone via a non-covalent interaction that is part of the cyclic oligomer's lipophilic central cavity. By inclusion in, an abiraterone or an inclusion complex containing a part of abiraterone can be formed. By forming a partial or complete inclusion complex containing abiraterone, CD or other cyclic oligomers can impart higher water solubility to abiraterone and enhance the bioavailability of abiraterone.

The cyclodextrins (CDs) of the present disclosure include α-CD containing 6 glucopyranose units, β-CD containing 7 glucopyranose units, and γ-CD (Loftsson,) containing 8 glucopyranose units. T., P. Jarho, M. Masson, and T. Jarvinen. 2005.'Cyclodextrins in drug delivery', Expert Opin Drug Deliv, 2: 335-51.), And derivatives thereof.

The CDs of the present disclosure may contain substitutions of one or more hydroxy groups. Without limitation of theory, substitution of hydroxy groups with hydrophobic or hydrophilic groups of CDs may be used to impart even higher water solubility to CDs by interfering with CD intermolecular hydrogen bonds. For example, hydroxypropyl substitution on β-CD to form hydroxypropyl β-cyclodextrin (HPBCD) (Fig. 38), respectively, increases the water solubility of β-CD from 18.5 mg / ml to> 600 mg / ml, respectively. (Loftsson, T., P. Jarho, M. Masson, and T. Jarvinen. 2005.'Cyclodextrins in drug delivery', Expert Opin Drug Deliv, 2: 335-51.). Thus, in some embodiments, the β-CD may contain one or more R groups with varying degrees of substitution at positions 2, 3, and 6 as shown in FIG. 38, for example. .. In the formula, R = CH ₂ CHOHCH ₃ or H.

For example, the pharmaceutical formulation is a cyclodextrin, eg, a cyclodextrin containing 6, 7, or 8 monomeric units, in particular an α-cyclodextrin, eg, CAVAMAX® W6 Pharma (Wacker Chemie AG, Germany). ), Β-cyclodextrin, eg, CAVAMAX® W7 Pharma (Wacker Chemie), or γ cyclodextrin, eg, CAVAMAX® W8 Pharma (Wacker Chemie). Cyclodextrin contains a (α-1,4) -linked α-D-glucopyranose dextrose unit that forms an acyclic structure with a lipophilic central cavity and a hydrophilic outer surface. Suitable cyclodextrins include hydroxypropyl β-cyclodextrins such as KLEPTOSE® HBP (Roquette, France) and Na sulfo-butyl ether β cyclodextrins such as DEXOLVE® 7 (Cyclolab, Ltd., Hungary). ) Is also included.

Derivatization may facilitate the use of cyclic oligomer excipients in thermodynamic formulations.

In particular, when used in a thermodynamic compounding process, the particle size of the cyclic oligomeric excipient may facilitate the compounding process. Derivatization, pretreatment, eg, pretreatment by slugging and / or granulation, may increase or decrease the particle size of the cyclic oligomeric excipient within the optimum range. For example, the average particle size of cyclic oligomeric excipients may increase by up to 500%, or up to 1,000%, 50% to 500%, or 50% to 1,000%. The average particle size of the cyclic oligomeric excipient may be reduced by up to 50%, or 90%, or 5% to 50%, or 5% to 90%.

The inclusion complex of the present disclosure may also be referred to as a host-guest inclusion complex, where the cyclic oligomer is the host and the abiraterone is the guest. For example, FIG. 37 shows a non-limiting example of a host-guest inclusion complex in a schematic form. In a non-limiting example, FIG. 37, left panel schematically illustrates a unit of a host molecule, eg, a cyclic oligomer, eg, cyclodextrin, eg, hydroxypropyl β cyclodextrin (HPBCD), in which. It contains the guest molecule abiraterone, or contains at least a portion of the abiraterone molecule. In another non-limiting example, FIG. 37, right panel schematically illustrates two units of a host molecule, eg, a cyclic oligomer, eg, cyclodextrin, eg, hydroxypropyl β cyclodextrin (HPBCD). It contains a guest molecule, abiraterone, or contains at least a portion of the abiraterone molecule.

The pharmaceutical formulations of the present disclosure may be prepared using thermodynamic formulations as described herein. Without limitation of theory, thermodynamic compounding of avilateron and cyclic oligomers provides more tightly with avilateron and cyclic oligomers than this thermodynamic compounding process makes possible using several other formulation methods. It may have an advantage in the formulation of the pharmaceutical formulations of the present disclosure, which can be mixed. In particular, for example, as discussed above, cyclodextrins have a truncated cone-like or toroid structure, with the larger and smaller openings of the toroid each having a secondary hydroxyl group in the solvent. The primary hydroxyl group is exposed. In some practices, without limitation to theory, thermodynamic formulations may allow abiraterone to be included in the truncated cone-like or toroidal structures of cyclodextrins. Thermodynamic formulations may increase the efficiency and / or percentage of the available abiraterone inside the cyclodextrin structure compared to other formulation methods. Therefore, inclusion of abiraterone inside a cyclodextrin may improve the solubility and bioavailability of abiraterone.

Accordingly, in some embodiments, the present disclosure relates to a method of forming a pharmaceutical formulation of abiraterone and a cyclic oligomer having an optimal drug loading amount of abiraterone in an inclusion complex using the cyclic oligomer.

The term "drug loading amount" generally refers to the amount of API incorporated into a pharmaceutical product. In particular, the term "drug loading amount" as used herein refers to the amount of abiraterone that can be included in the inclusion complex within a cyclic oligomer in a pharmaceutical formulation. In some embodiments, the method of forming the pharmaceutical formulation of the present disclosure comprising a thermodynamic formulation process increases the drug loading as compared to other methods of formulating the pharmaceutical formulation. This increases the amount of abiraterone that can be contained in the inclusion complex within the cyclic oligomer in the pharmaceutical formulation, and may correspondingly exist as an amorphous dispersion between the cyclic oligomers in the pharmaceutical formulation. It means that the amount of abiraterone that was not contained is reduced.

For example, in general, for solid dispersions, when the drug loading is less than the equilibrium solubility of the crystalline drug in the polymer carrier, the system is thermodynamically stable and the drug is molecularly contained in the polymer carrier matrix. It is dispersed to form a homogeneous system (Huang and Dai 2014). Such systems occur with very low drug loading and may not be practical for some drug-polymer carrier systems (Huang and Dai 2014). When the amount of drug loading in the solid dispersion is high, for example above the equilibrium solubility of the amorphous drug in the polymer carrier, such systems are very unstable, leading to spontaneous phase separation and crystallization, which leads to spontaneous phase separation and crystallization. May adversely affect the stability and performance of solid dispersions (Qian, Huang, and Hussain 2010). Moreover, when cyclic oligomers such as CDs are excipients for pharmaceutical formulations, it cannot be assumed that a small amount of drug loading will always be beneficial. Low drug loading means high CD content, which can interfere with drug absorption from the gastrointestinal tract and reduce bioavailability (Loftsson et et.). al. 2016; Loftsson and Brewster 2012). Similarly, the problems associated with high drug loading as discussed above also apply to pharmaceutical formulations containing APIs and cyclic oligomers. For example, when the API is present in greater than the equilibrium solubility of the amorphous drug in the cyclic oligomer support, such a system can become very unstable, leading to spontaneous phase separation and crystallization, thereby. It may adversely affect the stability and performance of pharmaceutical formulations. Therefore, it is important to identify the optimal drug loading amount when the carrier is a cyclic oligomer, eg HPBCD.

In some embodiments, the inclusion complex in the pharmaceutical formulation of the present disclosure is up to 10% by weight, up to 20% by weight, based on the total weight of the pharmaceutical formulation, including the weight of avilateron + the weight of the cyclic oligomer. May have up to 30%, 40%, 50%, 60%, 70%, 80%, or 90% by weight of Avilateron drug loading.

For example, in some embodiments, the inclusion complex of the pharmaceutical formulation of the present disclosure is up to 10% by weight, 20% by weight, based on the weight of the avilateron + the weight of the cyclic oligomer, eg, HPBCD. It may have a drug loading of up to% by weight, or up to 30% by weight, in which case the avilateron takes a substantially physically amorphous and chemically stable form (eg, Example 24). And 27).

As will be appreciated by those of skill in the art, for a given combination of abiraterone and cyclic oligomer, the percent weight of drug loading and abiraterone: by considering the molecular weight of each of the abiraterone and the cyclic oligomer (eg, in units of g / mol): The relationship with the molar ratio of cyclic oligomers can be calculated.

In some embodiments described herein, the molar ratio of guest molecule: host molecule of the inclusion complex is, for example, 1: 0.25 to 1:25, or, for example, about 2: 1, 1: 1, or. It may be 1: 2. Thus, in some aspects of the pharmaceutical formulations of the present disclosure, the abiraterone and cyclic oligomers are, for example, 1: 0.25 to 1:25, or, for example, about 2: 1, 1: 1, or 1: 2 abiraterone. : May be present in pharmaceutical formulations in molar ratio of cyclic oligomers. For example, in some embodiments of the pharmaceutical formulations of the present disclosure, abiraterone and HPBCD are pharmaceutical in molar ratios of abiraterone: HPBCD of 1.0: 2.2, 1.0: 1.0, 1.0: 0.6, 1.0: 0.4, and 1.0: 0.2. It may be present in the formulation. In some embodiments, the abiraterone and HPBCD may be present in the pharmaceutical formulation in a molar ratio of 1.0: 2.2 to 1.0: 0.6, or, for example, about 1: 2 abiraterone: HPBCD, in this case pharmaceutical. The pharmaceutical product contains amorphous abiraterone that is at least partially complexed with HPBCD (see, eg, Example 25). In some embodiments, without limitation to theory, a molar ratio of 1: 2 or about 1: 2 abiraterone: HPBCD may allow one molecule of abiraterone to be completely encapsulated inside two molecules of HPBCD. be. Similarly, without limitation to theory, in some embodiments, 10% or about 10% abiraterone: 90% or about 90% HPBCD drug loading amount is one molecule of abiraterone inside two molecules of HPBCD. It may be possible to completely enclose it.

In some embodiments, a formulation method that includes a thermodynamic formulation process is compared to a pharmaceutical formulation that has the same molar ratio of avilateron: cyclic oligomers that was formed using a method that does not include a thermodynamic formulation process. It increases the efficiency of inclusion complexation and thereby increases the stability of amorphous avilateron in pharmaceutical formulations. Without limitation of theory, thermodynamic formulations include thermodynamic compounding processes, whereas thermodynamic formulations may be able to increase stable abiraterone inclusion complex formation, at least partially inside the cyclic oligomers. No other formulation method may increase the amount of unencapsulated abiraterone present outside the cyclic oligomer.

Accordingly, in some embodiments, the present disclosure comprises an avilateron or a pharmaceutically acceptable salt, ester, derivative, analog, prodrug, hydrate, or solvate compound and cyclic oligomer excipient. At least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 99.9% of the cyclic oligomer as an inclusion complex. Provides an internal pharmaceutical formulation.

In some embodiments, the pharmaceutical formulations of the present disclosure formed using a method comprising a thermodynamic compounding process are encapsulated with avilateron inside a cyclic oligomer as compared to a method not comprising a thermodynamic compounding process. Can be increased to 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90%, or thermodynamic compounding process Up to 2 times, 3 times, 4 times, 5 times, 6 times, 7 times, 8 times, 9 times, up to 2 times, up to 3 times, up to 4 times, up to 5 times, up to 6 times, up to 9 times, compared to the method without Or it may be increased up to 10 times.

In some embodiments, the inclusion complex of the pharmaceutical formulation of the present disclosure may have increased stability in terms of both physical and chemical stability. As used herein, the term "stability" includes physical stability, eg, abiraterone being maintained in an amorphous state in a pharmaceutical formulation without crystallizing or recrystallizing the abiraterone. .. As used herein, the term "stability" also reduces chemical stability, eg, the incidence of API degradation, due to, for example, incompatibility with other excipients, heat exposure, and light exposure. Including that. For example, the inclusion complex of the present disclosure reduces abiraterone crystallization over time as compared to the amount of crystallization over time in a formulation containing abiraterone in an amorphous solid dispersion without abiraterone encapsulated in the inclusion complex. Maybe.

For example, the stability of the avilateron in the pharmaceutical formulation of the present disclosure is such that the method according to Examples 22-28, for example, the pharmaceutical formulation is heated and cooled at a selected temperature for a selected period of time. , Including, but not limited to, the heating tests described herein analyzed by X-ray diffraction (XRD), using methods known in the art and methods that can be identified by one of ordinary skill in the art by reading the present disclosure. Can be evaluated.

Without limitation, when each molecule of abiraterone is complexed with at least one cyclic oligomer, for example, at least a portion of the abiraterone molecule, as schematically shown in Figure 37, left panel. By encapsulation inside a single cyclic oligomer, each abiraterone can be thermally and kinically stabilized. Increasing the ratio of the cyclic oligomer to the abiraterone results in the inclusion of the abiraterone inside one or more, eg, two cyclic oligomers, in some embodiments, eg, as shown in FIG. 37, right panel. Will be possible. Recrystallization of abiraterone not encapsulated inside the cyclic oligomer can be detected as crystalline abiraterone by XRD analysis. For example, without limitation to theory, abiraterone and cyclic oligomers that can be recrystallized by heating followed by cooling and can be detected as a crystalline form of abiraterone using, for example, XRD analysis. The abiraterone in the pharmaceutical formulation was not encapsulated inside the cyclic oligomers, but may be an abiraterone that may exist as an amorphous abiraterone dispersed among the cyclic oligomers in the pharmaceutical formulation. ..

Thus, in some aspects of the pharmaceutical formulation of the present disclosure, in response to heating the pharmaceutical formulation to a temperature up to 90% of the melting point of the crystalline avilateron and cooling the pharmaceutical formulation to room temperature, the avilateron Less than 10%, less than 9%, less than 8%, less than 7%, less than 6%, less than 5%, less than 4%, less than 3%, less than 2%, less than 1%, or less than 0.1% can take crystalline form There is sex.

In some embodiments, the pharmaceutical formulations of the present disclosure formed using a method comprising a thermodynamic compounding process compare the stability of amorphous avilateron to a method not comprising a thermodynamic compounding process10 Increase up to%, up to 20%, up to 30%, up to 40%, up to 50%, up to 60%, up to 70%, up to 80%, up to 90%, or more, or stability of amorphous avilateron Up to 2x, 3x, 4x, 5x, 6x, 7x, 8x, 9x, or 10x compared to methods that do not include a thermodynamic compounding process. May increase to.

For stability analysis, one or more of the abiraterone: cyclic oligomers to identify the molar ratio of abiraterone: cyclic oligomers, which has an acceptable level of stability and results in the highest abiraterone drug loading amount in the pharmaceutical formulation. Analyzing the pharmaceutical formulations of the present disclosure formed using the molar ratio may be included.

In some embodiments, the acceptable level of stability may be substantially complete amorphicity when confirmed by X-ray diffraction, and may be substantially free of abiraterone recrystallization after heating. For example, less than 10%, less than 9%, less than 8%, less than 7%, less than 6%, less than 5%, less than 4%, less than 3%, less than 2%, less than 1%, or less than 0.1% after heating. There may be abiraterone recrystallization.

For example, in some embodiments, the pharmaceutical formulations of the present disclosure may remain substantially amorphous, eg, when confirmed by X-ray diffraction, and abiraterone recrystallization in response to heating to temperatures up to 150 ° C. It does not have to be substantially absent. For example, pharmaceutical formulations with inclusion complexes containing up to 20% abiraterone have substantially abiraterone recrystallization in response to heating to temperatures up to 150 ° C., for example when confirmed by X-ray diffraction. It may not be present (see, for example, Example 27).

Other methods that can be used to assess the stability of avilateron in the pharmaceutical formulations of the present disclosure include modulated differential scanning calorimetry (mDSC), Raman spectroscopy, and solid-state nuclear magnetic resonance. Resonance spectroscopy (ssNMR) is included (see, eg, Examples 22-28).

In general, the amorphous properties, or the degree of avilateron encapsulation inside the cyclic oligomer of the inclusion complex, may be analyzed using X-ray diffraction (XRD) and is a strong characteristic mainly characteristic of crystalline materials. It may not show a peak. The degree of amorphous properties, or encapsulation of avilateron inside the cyclic oligomer of the inclusion complex, is also determined by other methods described herein, such as Modulated Differential Scanning Calorimetry (mDSC), Solid State Nuclear Magnetic Resonance Spectroscopy (ssNMR). ), Raman spectroscopy, phase solubility analysis, stability analysis, in vitro dissolution test may be used for analysis. Examples of these methods are described in Examples 22-28 of the present disclosure. For example, the degree of avilateron-cyclic oligomer inclusion complex formation in pharmaceutical formulations may be demonstrated by a decrease in the intensity of drug melt absorption in differential scanning calorimetry or by the magnitude of peak shift in Raman spectroscopy. It may often be demonstrated by peak broadening in nuclear magnetic resonance spectroscopy.

The pharmaceutical formulations of the present disclosure may also include one or more additional excipients. These additional excipients may include, in particular, polymer excipients or combinations of polymeric excipients. Suitable polymer excipients may be water soluble. Suitable polymeric excipients may also be ionic or nonionic.

Suitable polymer excipients include cellulose-based polymers, polyvinyl-based polymers, or acrylate-based polymers. These polymers may have a wide variety of degrees of polymerization or functional groups.

Suitable cellulose-based polymers include alkyl celluloses such as methyl cellulose, hydroxyalkyl cellulose, or hydroxyalkyl alkyl cellulose. Suitable cellulose-based polymers include, specifically, hydroxymethyl cellulose, hydroxyethyl methyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxybutyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, such as METHODCEL ™ E3 and METHODCEL ™. ) E5 (Dow Chemical, Michigan, US); Ethyl Cellulose, eg ETHOCEL® (Dow Chemical), Butyrate Cellulose Acetate, Hydroxyethyl Cellulose, Sodium Carboxymethyl Cellulose, Hydroxypropyl Methyl Cellulose Acetate Succinate, eg AFFINISOL®. ) HPMCAS 126 G (Dow Chemical), Cellulose acetate, Cellulose phthalate acetate, eg AQUATERIC ™ (FMC, Pennsylvania, US), Carboxymethyl cellulose, eg, Carboxymethyl cellulose Sodium, Hydroxyethylmethyl cellulose, Hydroxypropyl Includes cellulose, hydroxyethyl cellulose, hydroxymethyl cellulose, crystalline cellulose, and any combination thereof.

Suitable polyvinyl-based polymers include polyvinyl alcohol, eg, polyvinyl alcohol 4-88, eg, EMPROVE® (Millipore Sigma, Massachusetts, US) polyvinylpyrrolidone, eg, LUVITEK® (BASF, Germany) and KOLLIDON® 30 (BASF), polyvinylpyrrolidone-co-vinyl acetate, poly (vinyl acetate) -co-poly (vinylpyrrolidone) polymers such as KOLLIDON® SR (BASF), poly (vinyl acetate). Phthalates such as COATERIC® (Berwind Pharmaceutical Services, Pennsylvania, US) or PHTHALAVIN® (Berwind Pharmaceutical Services), polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, eg SOLUPLUS® ( BASF), polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, such as SOLUPLUS® (BASF), rigid polyvinyl chloride, and any combination thereof.

Suitable acrylate-based polymers include acrylate and methacrylate copolymers, type A copolymers of methacrylic acid esters with ethyl acrylate, methyl methacrylate, and quaternary ammonium groups in a 1: 2: 0.1 ratio, such as EUDRAGIT®. ) RS PO (Evonik, Germany), poly (meth) acrylates with carboxylic acid functional groups, such as EUDRAGIT® S100 (Evonik), dimethylaminoethyl methacrylate-methacrylic acid ester copolymer, ethyl acrylate-methacrylic acid. Methyl Copolymer, Poly (Methyl Methacrylate Acrylate) (1: 1) Copolymer, Poly (Methyl Methacrylate) (1: 1) Copolymer, Poly (Methyl Methacrylate) (1: 2) Copolymer, Poly (Methyl Methacrylate-co-Acrylate) Ethyl acetate (1: 1), eg EUDRAGIT® L-30-D (Evonik), poly (methacylic acid-co-ethyl acrylate) (1: 1), eg EUDRAGIT ( Registered Trademarks) L100-55 (Evonik), Poly (butylmethacylate-co- (2-dimethylaminoethyl) Methacrylate-co-Methyl methacrylate (1: 2: 1), eg EUDRAGIT® ) EPO (Evonik), a methacrylate-ethacrylate copolymer, such as KOLLICOAT MAE 100-55 (BASF), polyacrylate, polymethacrylate, and any combination thereof.

Certain polymeric excipients are particularly well suited for use alone as secondary excipients in combination with cyclic oligomer primary excipients. The secondary polymer excipient may be water soluble. The polymer secondary excipient may be ionic or nonionic. Suitable secondary nonionic polymer excipients include hydroxypropylmethylcellulose, eg, METHOD Chemical, Michigan, US, and METHOD Chemical, and polyvinylpyrrolidone, eg, Includes KOLLIDON® 90 (BASF, Germany). Suitable secondary ionic polymer excipients include hydroxypropylmethylcellulose acetate succinates such as AFFINISOL® HPMCAS 716 G (Dow Chemical), AFFINISOL® HPMCAS 912 G (Dow Chemical), and AFFINISOL® HPMCAS 126 G (Dow Chemical), polyvinyl acetate phthalate, eg PHTHALAVIN® (Berwind Pharmaceutical Services), methacrylic acid based polymers such as methacrylic acid-etacrilate copolymers, eg EUDRAGIT ( Includes L100-55 (Evonik, Germany), and any combination thereof.

One particularly well-suited secondary excipient includes hydroxypropylmethylcellulose acetate succinate. The hydroxypropylmethylcellulose acetate succinate may have an acetate substitution of 5-14%, more specifically 10-14%, more specifically 12%. The hydroxypropylmethylcellulose acetate succinate may have a succinate substitution of 4-18%, more specifically 4-8%, more specifically 6%.

The polymer excipient may contain only one type of polymer, or the pharmaceutical formulations of the present disclosure may contain a combination of polymer excipients.

None of the excipients, including any cyclic oligomer excipient or any polymeric excipient found in the pharmaceutical formulations of the present disclosure, may contain significant levels of impurities. For example, the excipients in the pharmaceutical formulations of the present disclosure are less than 1.0% by weight, 0.75% by weight, compared to the total weight of excipients and impurities compared to standard substances at known concentrations in mg / mL. May have impurities less than%, less than 0.5% by weight, less than 0.1% by weight, less than 0.05% by weight, or less than 0.01% by weight. Impurities may include excipient degradation products, such as thermal degradation products.

The pharmaceutical formulations of the present disclosure may also contain one or more lipids. The pharmaceutical formulations of the present disclosure may be formulated using one or more lipid techniques. The lipid may be a synthetic lipid, a semi-synthetic lipid, or a natural lipid. Lipids may be anionic, cationic, or neutral. Exemplary lipids include fats, fatty acids such as saturated, monosaturated, polyunsaturated, ω-3, α-linolenic acid (ALA), eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), ω. -6, arachidonic acid (AA), linoleic acid, conjugated linoleic acid (CLA), and trans fatty acids, short chain fatty acids (SCFA) such as α-lipoic acid, medium chain fatty acids (MCFA), long chain fatty acids (LCFA) , Ultra-long chain fatty acids (VLCFA), monoglycerides, diglycerides, triglycerides, phospholipids such as lecithin (phosphatidylcholine), sterol, cholesterol, phytosterol (plant sterol and stanol), carotenoids such as astaxanthin, lutein and zeaxanthin, lycopene, Includes vitamin A-related carotenoids, waxes, and any combination thereof.

The pharmaceutical formulations of the present disclosure may be in the form of amorphous avilateron and excipients. The abiraterone may contain less than 5% crystalline abiraterone, may contain less than 1% crystalline abiraterone, or may not contain crystalline abiraterone. Amorphous properties of pharmaceutical formulations may be confirmed using X-ray diffraction (XRD) and may not show the strong peaks characteristic of predominantly crystalline materials.

The pharmaceutical formulations of the present disclosure are formed by any suitable method for making an amorphous solid dispersion, eg, thermodynamic formulation, hot melt extrusion, or spray drying, among others described herein. Can be done. Thermodynamic formulations may be particularly useful for excipients that decompose in hot melt extrusions or for excipients that do not have an organic solvent system in common with abiraterone to facilitate spray drying.

As discussed above, thermodynamic formulations may also be particularly useful for increasing the encapsulation yield of abiraterone inside the cyclic oligomers of the inclusion complex as compared to other formulation methods. Without being limited to theory, thermodynamic formulations result in increased compounding power, eg, shearing force, and avilateron within the lipophilicity of cyclic oligomers than is possible using other formulation methods. It may facilitate an increase in inclusion complex formation. Therefore, the thermodynamic formulation is encapsulated in the cyclic oligomer in the inclusion complex of the present disclosure after formulation, as compared to the amount of avilateron that is not encapsulated in the cyclic oligomer after formulation using other formulation methods. May reduce the amount of unfilled avilateron. In some embodiments, the unencapsulated abiraterone may form an amorphous abiraterone dispersed in the pharmaceutical formulation as an amorphous solid dispersion. In some embodiments, the thermodynamic formulation causes up to 5%, up to 10% abiraterone inclusion complex formation inside the cyclic oligomer, rather than the abiraterone inclusion complex formation that can be achieved using other formulation methods. , Up to 15%, up to 20%, up to 25%, up to 30%, up to 35%, up to 40%, up to 45%, up to 50%, up to 55%, up to 60%, up to 65%, up to 70%, 75 May be increased up to%, up to 80%, up to 85%, up to 90%, up to 95%, or up to 100%. In some embodiments, the thermodynamic formulation doubles the inclusion complex formation of abiraterone contained within the cyclic oligomer, rather than the abiraterone inclusion complex formation that can be achieved using other formulation methods, 3 It may be increased up to times, up to 4 times, up to 5 times, up to 6 times, up to 7 times, up to 8 times, up to 9 times, or up to 10 times. Therefore, the thermodynamic formulation is abiraterone in the inclusion complex with cyclic oligomers at a higher concentration than that achieved using other formulation methods, while maintaining solubility, bioavailability, or both. May facilitate the formulation of.

The pharmaceutical formulations of the present disclosure containing amorphous avilateron are 0.01N HCl and bio-related media such as simulated gastric juice (SGF), fasting simulated intestinal juice (FaSSIF), and feeding simulated intestinal juice (FeSSIF). When demonstrated by elution in at least one of, it may dissolve more easily in the patient's gastrointestinal tract than a pharmaceutical formulation containing pure crystalline Avilaterone.

In some embodiments, the pharmaceutical formulations of the present disclosure containing up to 10 wt% amorphous avirateron are 0.01N HCl, as well as simulated gastric juice (SGF), fasting simulated intestinal juice (FaSSIF), and simulated intestinal juice during feeding. At least 13 to 17 times more in the patient's gastrointestinal tract, eg, than a pharmaceutical formulation containing pure crystalline avirateron, when demonstrated by elution in at least one of the bio-related mediums such as (FeSSIF). , May have 15.7-fold increased elution. In some embodiments, the pharmaceutical formulations of the present disclosure containing up to 20% by weight of amorphous avilateron are 0.01N HCl, as well as simulated gastric juice (SGF), fasting simulated intestinal juice (FaSSIF), and simulated intestinal juice during feeding. At least 10-14 times in the patient's gastrointestinal tract, eg, than a pharmaceutical formulation containing pure crystalline avirateron, when demonstrated by elution in at least one of the bio-related mediums such as (FeSSIF). , May have 12.1 times increased elution. In some embodiments, the pharmaceutical formulations of the present disclosure containing up to 30% by weight of amorphous avilateron are 0.01N HCl, as well as simulated gastric juice (SGF), fasting simulated intestinal juice (FaSSIF), and simulated intestinal juice during feeding. At least 5-9 times in the patient's gastrointestinal tract, eg, than a pharmaceutical formulation containing pure crystalline avilateron, when demonstrated by elution in at least one of the bio-related mediums such as (FeSSIF). , May have 7.2-fold increased elution. In some embodiments, the pharmaceutical formulations of the present disclosure containing up to 40% by weight of amorphous avilateron are 0.01N HCl, as well as simulated gastric juice (SGF), fasting simulated intestinal juice (FaSSIF), and simulated intestinal juice during feeding. At least 3-7 times in the patient's gastrointestinal tract, eg, than a pharmaceutical formulation containing pure crystalline avirateron, when demonstrated by elution in at least one of the bio-related mediums such as (FeSSIF). , May have 5.0-fold increased elution. In some embodiments, the pharmaceutical formulations of the present disclosure containing up to 50% by weight of amorphous avilateron are 0.01N HCl, as well as simulated gastric juice (SGF), fasting simulated intestinal juice (FaSSIF), and simulated intestinal juice during feeding. At least 2-5 times in the patient's gastrointestinal tract, eg, than a pharmaceutical formulation containing pure crystalline avilateron, when demonstrated by elution in at least one of the bio-related mediums such as (FeSSIF). , 3.1-fold increased elution (see Example 28).

Alternatively, the pharmaceutical formulation may be incorporated into a final dosage form that modifies or prolongs the release of abiraterone. This may include extended release, delayed release, and / or pulsatile release profiles and the like. The pharmaceutical formulation may be incorporated into a tablet form containing a hydrophilic matrix that forms a hydrogel swollen in the gastric environment. This hydrogel formation is intended to (1) keep the tablet in the stomach and (2) delay the release of abiraterone so that the drug is released continuously for about 24 hours. More specifically, this dosage form may be an extended release oral drug dosage form for releasing avilateron into the patient's stomach, duodenum, and small intestine, (i) increasing the size of the particles, fasting / feeding. By absorbing water from the gastric fluid to promote gastric retention in the stomach of the patient whose mode is induced, it swells without being dimensionally restricted; (ii) slowly over several hours. Avilaterone diffuses into or begins when the polymer corrodes and diffusion or corrosion comes into contact with gastric fluid; as used herein, Avilateron ASD is important for solubilization of Avilateron during diffusion or corrosion; and (iii) above. Dispersed within a polymer or combination of polymers, avilateron or pharmaceutically acceptable thereof, that releases avilateron into the patient's stomach, duodenum, and small intestine as a result of diffusion or polymer corrosion at a rate corresponding to the duration of the Includes one or more solid particles consisting of salts or prodrugs or hydrates or solvates. Exemplary polymers include polyethylene oxide, alkyl substituted cellulose materials and combinations thereof, such as high molecular weight polyethylene oxide, and high molecular weight or high viscosity hydroxypropylmethyl cellulose materials. Particularly well-suited polymer combinations are polyethylene oxide POLYOX ™ WSR 301, which is used in the final tablet form at about 24% w / w, and hydroxypropyl, which is used in the final tablet form at about 18% w / w. Includes a combination of Methyl Cellulose Methocel® E4M. This dosage form is intended to yield a pharmacokinetic profile with a low C _max to C _min ratio so that human plasma concentrations remain within the treatable time range during the treatment period. This abiraterone pharmacokinetic profile is expected to result in more effective cancer treatment with similar or few side effects.

The above example is the only example in which a long-term release of solubility-enhanced abiraterone ASD can be achieved, thereby minimizing the C _max to C _min ratio in the patient. Another example is a component designed to immediately release soluble-enhanced abiraterone ASD into the stomach, and one or more additional components designed to release abiraterone pulses to different regions of the intestinal tract. It is a pulsatile release dosage form containing. This can be achieved by applying a pH sensitive coating to one or more abiraterone ASD-containing components, the coating dissolving and dissolving the active ingredient in different regions along the GI tube depending on the environmental pH. Designed to emit. These functionally coated components may also contain acidifying agents that lower the microenvironmental pH and promote the solubility and elution of abiraterone.

In addition, there are a myriad of sustained release techniques that can be applied to generate a long-term abiraterone release profile when starting with the solubility-enhanced abiraterone ASD compositions disclosed herein. The application of conventional controlled drug release techniques to crystalline abiraterone or abiraterone acetate does not result in sufficient drug release along the GI tube due to insufficient solubility of these forms of the compound, and thus the abiraterone ASD composition. However, it is important to note that energizing this approach.

In the pharmaceutical formulation of the present disclosure, the cyclic oligomer may be the only excipient. The pharmaceutical formulation may contain 1% to 50% by weight of amorphous abiraterone, in particular abiraterone and 50% to 99% by weight of one or more cyclic oligomeric excipients. Alternatively, the pharmaceutical formulation may contain at least 5%, at least 10%, or at least 20% by weight amorphous abiraterone, in particular abiraterone. Alternatively, the pharmaceutical formulation may contain at least 60% or at least 90% by weight of one or more cyclic oligomer excipients.

In another pharmaceutical formulation of the present disclosure, the cyclic oligomer may be a primary excipient. The pharmaceutical formulation may contain 1% to 50% by weight of amorphous abiraterone, in particular abiraterone and 50% to 99% by weight of the cyclic oligomer primary excipient. Alternatively, the pharmaceutical formulation may contain at least 5%, at least 10%, or at least 20% by weight amorphous abiraterone, in particular abiraterone. Alternatively, the pharmaceutical formulation may contain at least 60% by weight cyclic oligomer excipient. The pharmaceutical formulation may further contain at least 1% of the secondary excipient, in particular the polymeric secondary excipient.

In another pharmaceutical formulation of the present disclosure, the cyclic oligomer may be a secondary excipient, and the pharmaceutical formulation may further comprise a primary excipient, eg, a polymeric primary excipient. Pharmaceutical formulations are 1% to 50% by weight amorphous abiraterone, in particular abiraterone, 50% to 99% by weight primary excipient and 50% to 99% by weight cyclic oligomer secondary shaping. It may contain an agent. Alternatively, the pharmaceutical formulation may contain at least 5%, at least 10%, or at least 20% by weight amorphous abiraterone, in particular abiraterone.

The pharmaceutical formulations of the present disclosure are avilateron and cyclic oligomer excipients, in particular hydroxypropyl β cyclodextrin excipients 1: 0.25 to 1:25, eg, at least 1: 2 avilateron: cyclic oligomer excipients. It may be contained in the molar ratio of.

In certain cases, the pharmaceutical formulations of the present disclosure are 1% to 50%, in particular at least 10% by weight of the avilateron form, 80% by weight of the hydroxypropyl β cyclodextrin primary excipient, and 1% to 49%. In particular, it may be an amorphous dispersion of at least 10% by weight of hydroxypropylmethylcellulose acetate succinate secondary excipient.

The pharmaceutical formulations of the present disclosure have a therapeutic effect equal to or greater than that of amorphous abiraterone or crystalline abiraterone acetate, eg, ZYTIGA®, when ingested on an empty stomach. It may contain a sufficient amount of amorphous abiraterone to achieve bioavailability, C _min , C _max , or T _max . The pharmaceutical formulations described herein may significantly improve the solubility of abiraterone, which may promote improvements in therapeutic effect, bioavailability, C _min , C _max , or T _max .

"Therapeutic effect" may be measured by a decrease in measurable PSA levels throughout the course of treatment, eg, throughout the course of one month of treatment. To ascertain "therapeutic effect," other scientifically recognized therapeutic effect scales, such as those used in the process of obtaining regulatory approval, in particular the FDA, can also be used.

"Bioavailability" is measured herein as the area under the curve (AUC) of drug plasma concentration from the administered unit dosage form. Absolute bioavailability is the bioavailability of an oral composition compared to an intravenous reference that is expected to deliver 100% of its activity to the systemic circulation. The insolubility of abiraterone interferes with intravenous delivery. Therefore, the absolute bioavailability of abiraterone cannot be known. The absolute bioavailability of ZYTIGA® when administered on an empty stomach as approved should be less than 10% as its AUC increases 10-fold when administered with a high-fat diet. The increased bioavailability of ZYTIGA® when administered with a high-fat diet is presumed to be the result of improved abiraterone acetate solubility in the fed state. For ease of comparison, bioavailability in the present disclosure may be measured on an empty stomach, for example, at least 2 hours after the last ingestion of food and at least 1 hour before the next ingestion of food. be.

For example, the relative bioavailability of abiraterone in the pharmaceutical formulations of the present disclosure may be at least 500% greater, even at least 1,000% greater, as compared to ZYTIGA® or equivalent crystalline abiraterone acetate. May be good.

For example, as exemplified in Example 28, the pharmaceutical formulations of the present disclosure having abiraterone up to 10% by weight are in a larger amount of crystalline abiraterone or crystalline abiraterone acetate, eg, abiraterone when ingested on an empty stomach. May result in up to 4-fold increase in bioavailability of abiraterone compared to ZYTIGA®. The pharmaceutical formulations of the present disclosure having up to 20% by weight of abiraterone are of abiraterone as compared to abiraterone or crystalline abiraterone acetate in greater amounts than abiraterone when ingested on an empty stomach, eg, ZYTIGA®. May result in up to 3x increase in bioavailability. The pharmaceutical formulations of the present disclosure having up to 30% by weight of abiraterone are compared to a larger amount of crystalline abiraterone or crystalline abiraterone acetate, eg, ZYTIGA®, when ingested on an empty stomach. It may result in up to a 2-fold increase in the bioavailability of abiraterone (see, eg, Example 28).

As shown in Example 28, in some embodiments, the relative in vitro elution performance of the pharmaceutical formulation containing amorphous avilateron decreased as the drug loading increased. Without limitation of theory, this may be due to a decrease in abiraterone-cyclic oligomer inclusion complex formation, and thus a decrease in abiraterone solubility enhancement and an increase in drug loading.

In particular, the pharmaceutical formulations of the present disclosure provide the same therapeutic effect or bioavailability as 1000 mg of crystalline abiraterone acetate, eg, ZYTIGA®, in patients when taken once daily on an empty stomach. May contain a sufficient amount of amorphous abiraterone. Such pharmaceutical formulations may also include a glucocorticoid replacement API, eg, a 5 mg glucocorticoid replacement API.

Alternatively, the pharmaceutical formulations of the present disclosure provide the same therapeutic effect or bioavailability as 500 mg of crystalline abiraterone acetate, eg, ZYTIGA®, in a patient when taken twice daily on an empty stomach. May contain a sufficient amount of amorphous abiraterone. Such pharmaceutical formulations may also include a glucocorticoid replacement API, eg, a 5 mg glucocorticoid replacement API.

The pharmaceutical formulations of the present disclosure may be for oral administration and may be further processed with or without further formulation to facilitate oral administration.

The pharmaceutical formulations of the present disclosure may be further processed into solid dosage forms suitable for oral administration, such as tablets or capsules.

To further increase the therapeutic effect, bioavailability, C _min , or C _max of avilateron, the pharmaceutical formulations of the present disclosure are further amounts of primary, secondary (or tertiary, etc.) excipients such as hydroxy. It may be combined with a propylmethylcellulose acetate secondary excipient, or another suitable elevated polymer that is not part of the pharmaceutical formulation to produce a solid dosage form.

Concentration-increasing polymers suitable for use in solid dosage forms may contain compositions that do not interact adversely with abiraterone. The increasing concentration polymer may be neutral or may be ionizable. The increasing concentration polymer is at least 0.1 mg / mL over at least part or all of the pH range 1-8, in particular at least part or all of the pH range 1-7, or at least part or all of the pH range 7-8. May have water solubility. When the solid dosage form is dissolved in 0.01N HCl and a bio-related medium, such as simulated gastric juice (SGF), fasting simulated intestinal juice (FaSSIF), or fasting simulated intestinal juice (FeSSIF), the increasing concentration polymer is biogenic. The maximum concentration of avilateron dissolved in the relevant medium may be increased by at least 1.25 times, at least 2 times, or at least 3 times compared to the same solid dosage form without the increasing polymer. When a similar maximal increase in abiraterone concentration is observed in the bio-related medium when additional primary or secondary (or tertiary, etc.) excipients that are not present in the pharmaceutical formulation are added to the dosage form. There is.

B. Method of Formulating a Pharmaceutical Formula The pharmaceutical formulation of the present disclosure may be prepared using a thermodynamic formulation, which is a method of blending the components until the components are melt-blended. Thermodynamic formulations may be particularly useful for formulating thermosensitive or thermally unstable components. Thermodynamic formulations can provide short processing times, low processing temperatures, fast shear rates, and the ability to formulate thermally incompatible materials.

To form the pharmaceutical formulations of the present disclosure, thermodynamic formulations are performed in a thermodynamic chamber using one or more velocities during a single formulation operation per batch of ingredients. May be

The thermodynamic chamber comprises a chamber with an inner surface and a shaft extending into or penetrating the chamber. An extension extends from the shaft into the chamber and may extend close to the inner surface of the chamber. The extension is often rectangular in cross section, eg, in the shape of a blade, and has a facial portion. The components are blended by rotating the shaft during thermodynamic blending. For example, the particles of the component are formulated to collide with the inner surface of the chamber or the surface portion of the extension. The shear force of this collision causes crushing of the components, heating by friction, or both, and the rotating shaft energy is converted into heating energy. Any heating energy generated during the thermodynamic formulation is released from the mechanical energy input. The thermodynamic formulation is done without an external heat source. The thermodynamic chamber and the ingredients to be blended are not preheated before starting the thermodynamic blending.

The thermodynamic chamber may be equipped with a temperature sensor to measure its temperature, whether it is a component inside the thermodynamic chamber or not.

To realize thermodynamic formulations of avilateron and excipients, as well as any other component of the pharmaceutical formulations of the present disclosure, eg, additional APIs, eg, glucocorticoid supplement APIs, additional excipients, or both. During the thermodynamic formulation, the average temperature of the thermodynamic chamber may rise to a pre-defined final temperature over the period of the thermodynamic formulation. The pre-defined final temperature may be such that decomposition of abiraterone, excipients, or other components is avoided or minimized. Similarly, the rate of use of one or more of the thermodynamic formulations may be such that thermal decomposition of abiraterone, excipients, or other components is avoided or minimized. As a result, abiraterone, excipients, or other components of the solid amorphous dispersion may be free of significant impurities.

The average maximum temperature in a thermodynamic chamber during a thermodynamic formulation is avilateron or any other API present, one or all excipients, or one or all other components of an amorphous solid dispersion. , Or any combination of components or sub-combination that may be below the glass transition temperature, melting point, or molten transition point.

The pressure, duration, and other environmental conditions of the thermodynamic formulation, such as pH, moisture, buffers, ionic strength of the components being mixed, and exposure to gases such as oxygen are also avilateron or other present. Any API, one or all excipients, or one or all other components may be such that degradation is avoided or minimized.

The thermodynamic formulation may be batch or semi-continuous, depending on the volume of the product. When performed in batch, semi-continuous, or continuous manufacturing processes, each thermodynamic compounding step is less than 5 seconds, less than 10 seconds, less than 15 seconds, less than 20 seconds, less than 25 seconds, less than 30 seconds, less than 35 seconds. , Less than 40 seconds, less than 45 seconds, less than 50 seconds, less than 55 seconds, less than 60 seconds, less than 70 seconds, less than 100 seconds, less than 120 seconds, less than 240 seconds, or less than 300 seconds.

Variations in thermodynamic formulation may be used depending on the amorphous solid dispersion and its constituents. For example, the thermodynamic chamber is operated at a first speed to achieve the first process parameters and then at a second speed in the same thermodynamic compounding process to achieve the final process parameters. May occur. In another example, the thermodynamic chamber may be operated at more than two speeds, or only at two speeds, but at more than two time internals, eg, the first. It may be operated at a speed of 1, then at a second speed, and then again at a first speed.

Prior to thermodynamic compounding, the abiraterone component may be in crystalline or semi-crystalline form.

In another variation, the particle size of abiraterone or other APIs is reduced prior to thermodynamic formulation. This may be accomplished by grinding, eg, by dry grinding the crystalline form of avilateron or other APIs to a small particle size prior to thermodynamic formulation, and prior to thermodynamic formulation, avilateron or other. It may be accomplished by wet grinding the crystal form of the API with a pharmaceutically acceptable solvent to reduce the particle size, and prior to thermodynamic compounding, the crystal form of avilateron or other APIs may be avilateron or other. It may be accomplished by melting milling with at least one excipient that has limited compatibility with the crystalline form of the API to reduce the particle size.

Another variation involves grinding the crystal form of avilateron or other API in the presence of excipients to produce a regular mixture, in which case avilateron or other API particles are on the surface of the excipient particles. , Excipient particles adhere to the surface of API particles, or both.

Thermodynamically formulated amorphous solid dispersions may exhibit substantially complete amorphousness.

The pharmaceutical formulations of the present disclosure may be formulated without a solvent. For example, the pharmaceutical formulations of the present disclosure may be prepared using a thermodynamic formulation without solvent. Accordingly, the pharmaceutical formulations of the present disclosure prepared by thermodynamic formulation may have no solvent in the pharmaceutical formulation or its tablets and contain impurities in the pharmaceutical formulation or its tablets. It may not be present.

In certain embodiments, the pharmaceutical formulations of the present disclosure prepared by thermodynamic formulation may eliminate abiraterone prodrugs such as abiraterone acetate.

In certain embodiments, the pharmaceutical formulation of the present disclosure prepared by thermodynamic formulation may comprise an avilateron prodrug, such as avilateron acetate, in which case the pharmaceutical formulation is in the pharmaceutical formulation or a tablet thereof. May have no solvent and may have no solvent-containing impurities in the pharmaceutical formulation or its tablets.

In some embodiments, the formulation in a thermodynamic mixer results in up to 10%, up to 20%, 30% of the avilateron encapsulation inside the cyclic oligomer compared to methods that do not involve the thermodynamic compounding process. Pharmaceutically containing an inclusion complex of avilateron and cyclic oligomer excipient increased up to%, up to 40%, up to 50%, up to 60%, up to 70%, up to 80%, or up to 90%, or more. Bring the formulation.

In some embodiments, the formulation in a thermodynamic mixer doubles, triples, and 4 times the encapsulation of avilateron inside the cyclic oligomer compared to methods that do not involve the thermodynamic compounding process. It yields a pharmaceutical formulation containing an inclusion complex of avilateron and a cyclic oligomer excipient increased up to fold, up to 5 times, up to 6 times, up to 7 times, up to 8 times, up to 9 times, or up to 10 times.

The pharmaceutical formulations of the present disclosure may be prepared using hot melt extrusion. The hot melt extrusion heats the excipient blend to a molten state, which is then extruded through an orifice, where the extruded product is formed to its final form and solidifies upon cooling. The blend is transported through various heating compartments, typically by a screw mechanism. The screw is rotated by a variable speed motor inside a cylindrical barrel where there is only a small gap between the outer diameter of the screw and the inner diameter of the barrel. In this arrangement, a high shear force is generated on the barrel wall and during the screw flight, which allows the various components of the powder blend to mix well and deaggregate.

Hot melt extrusion instruments are typically single-screw or twin-screw appliances, but may consist of more than two screw elements. A typical hot melt extrusion appliance is continuously provided with a mixing / transporting compartment, a heating / melting compartment, and a pumping compartment up to the orifice. In the mixing / transport compartment, the powder blend is mixed and the shear forces between the screw element and the barrel reduce the agglomerates to the primary particles. In the heated / melted compartment, the temperature is at or above the melting point or glass transition temperature of the thermal binder in the blend so that the transport solid melts as it passes through the compartment. The heat binder in this situation represents an inert excipient, typically a polymer that is solid at ambient temperature but melts or becomes semi-fluid when exposed to high heat or pressure. .. The heat binder acts as a matrix in which abiraterone and other APIs are dispersed, or as an adhesive that binds abiraterone and other APIs so that a continuous composite is formed at the exit. Once in the melted state, the homogenized blend is pumped to the orifice through another heating compartment that maintains the melted state of the blend. At the orifice, the molten blend may be formed into chains, cylinders, or thin films. The extruded product is then typically solidified by an air cooling process. Once solidified, the extrude may then be further processed to form pellets, spheres, fines, tablets and the like.

The pharmaceutical formulations disclosed herein due to hot melt extrusions may have a uniform shape and density and may not exhibit significantly altered solubility or functionality of any excipient. Aviraterone, excipients, or other ingredients in pharmaceutical formulations may be free of significant impurities.

In certain embodiments, the pharmaceutical formulations of the present disclosure prepared by hot melt extrusion may eliminate abiraterone prodrugs such as abiraterone acetate.

In certain embodiments, the pharmaceutical formulation of the present disclosure prepared by hot melt extrusion may comprise an avilateron prodrug, such as avilateron acetate, in which case the pharmaceutical formulation is in the pharmaceutical formulation or a tablet thereof. May have no solvent, and may have no impurities containing the solvent in the pharmaceutical product or its tablets.

The pharmaceutical formulations of the present disclosure may be prepared using spray drying. In the spray drying process, components containing abiraterone and excipients and any other API or excipient are dissolved in a common solvent that dissolves the components to produce a mixture. After the ingredients have dissolved, the solvent is rapidly removed from the mixture by placing it in a spray dryer and evaporating, resulting in the formation of a solid amorphous dispersion of the ingredients. For rapid solvent removal, (1) place in a spray dryer and maintain pressure in a partial vacuum (eg 0.01-0.50 atm); (2) mix the mixture with a warm dry gas, or (3) (1). ) And (2). In addition, some or all of the heat required for solvent evaporation may be provided by heating the mixture.

Suitable solvents for spray drying may be any organic compound in which abiraterone and the primary excipient and any additional API or excipient are manually soluble. The solvent may also have a boiling point of 150 ° C. or lower. In addition, the solvent must be removed from the dispersion to acceptable levels according to The International Committee on Harmonization (ICH) guidelines, which show relatively low toxicity and are incorporated herein by reference. Further treatment steps, such as tray-drying after the spray drying process, may be used to remove the solvent to a sufficiently low level.

Suitable solvents include alcohols such as methanol, ethanol, n-propanol, isopropanol, and butanol; ketones such as acetone, methyl ethyl ketone and methyl isobutyl ketone; esters such as ethyl acetate and propyl acetate; and various other. Solvents such as acetonitrile, methylene chloride, toluene, and 1,1,1-trichloroethane are included. Low volatile solvents such as dimethylacetamide or dimethyl sulfoxide may also be used. Solvent mixtures may also be used, as well as with water as long as the abiraterone, excipients, and any other API or excipient in the pharmaceutical formulation show sufficient solubility to be spray dried. Mixtures may also be used.

The abiraterone, excipients, or other components of the pharmaceutical formulation disclosed herein due to spray drying may be free of significant impurities.

In certain embodiments, the pharmaceutical formulations of the present disclosure may be prepared by spray drying and may eliminate abiraterone prodrugs such as abiraterone acetate.

In certain embodiments, the pharmaceutical formulation of the present disclosure may be prepared by spray drying and may include an avilateron prodrug such as avilateron acetate, in which case the pharmaceutical formulation may be a pharmaceutical formulation or a tablet thereof. May have no solvent in it, and may have no solvent-containing impurities in the pharmaceutical formulation or its tablets.

The pharmaceutical formulations of the present disclosure are those that can be identified by one of ordinary skill in the art by reading the present disclosure, such as wet mass extrusion, high-strength mixing, high-strength mixing with a solvent, ball milling, ball milling with a solvent, or Prepared by combining avilateron with a cyclic oligomeric excipient using other methods including, but not limited to, any solvent casting or forming process using a forming process and a high mixing step. May be done. Abiraterone, excipients, or other components of the pharmaceutical formulations disclosed herein provided by either the methods described herein or those that can be identified by one of ordinary skill in the art by reading this disclosure. May be free of significant impurities.

In certain embodiments, it is prepared, in particular, by wet mass extrusion, high intensity mixing, high intensity mixing with solvent, ball milling, ball milling with solvent, or any solvent casting or forming process and high mixing step. The pharmaceutical formulations disclosed in this disclosure may exclude abiraterone prodrugs such as abiraterone acetate.

In certain embodiments, the pharmaceutical formulations of the present disclosure prepared by wet mass extrusion, high intensity mixing, high intensity mixing with solvent, ball milling, ball milling with solvent are avilateron pros such as avilateron acetate. May contain drugs, in which case the pharmaceutical formulation may not have a solvent in the pharmaceutical formulation or its tablets, or it may have an impurity containing the solvent in the pharmaceutical formulation or its tablets. May not be.

After the pharmaceutical formulation disclosed herein is formulated, an amount suitable for providing a given unit dosage form may be further processed, eg, to give an orally administrable form. .. This further treatment may include combining the pharmaceutical formulation as the internal phase with the external phase, if desired, along with tableting or encapsulation into the capsule by a tableting press. The external phase may include, for example, an additional amount of excipient or concentration increasing polymer to further improve therapeutic effect, bioavailability, C _min , or C _max .

In some examples, the pharmaceutical formulation may be tableted and then coated with a composition containing another API, such as a glucocorticoid supplement API.

C. How to administer pharmaceutical products
ZYTIGA®, an FDA-approved form of crystalline abiraterone acetate, is administered to prostate cancer patients on an empty stomach at a full dose of 1,000 mg once daily as multiple unit dosage form tablets. The bioavailability of ZYTIGA® under these conditions is estimated to be <10%.

Recent studies have shown that the low oral bioavailability of ZYTIGA® may be responsible for inadequate clinical outcomes in a significant portion of the patient population. This is demonstrated by correlating steady-state minimum serum levels (C _min ) with decreased PSA levels. Decreased PSA predicts improved clinical outcomes when treating mCRPC with ZYTIGA®. Initial responses, such as a> 30% drop in PSA from baseline by 4 weeks, are associated with prolonged overall survival. Robust responses, such as a> 50% drop in PSA from baseline at 12 weeks, are associated with prolonged overall survival. However, a significant portion of ZYTIGA® patients do not reach robust PSA reduction.

In a phase 3 study (COU-AA-302) in naive chemotherapy patients, 38% of the subjects (208 of 542) followed the Prostate Cancer Clinical Trials Working Group (PCWG2) criteria. Did not reach a> 50% reduction in PSA. In a phase 3 study (COU-AA-301) in pre-docetaxel-treated patients, 61% of patients (632 of 790) did not reach a> 50% reduction in PSA according to PCWG2 criteria. In a phase 3 study (AFFIRM) of enzalutamide in patients treated with pre-docetaxel, patients who were on progress taking enzalutamide were subsequently offered rescue therapy with ZYTIGA®. Only 8% of patients (3 out of 37) achieved a PSA reduction of> 50%.

A good PSA response with ZYTIGA® treatment is associated with patients with high abiraterone C _min . In a tumor inhibition model created for pooled data from the COU-AA-301 and COU-AA-302 Phase 3 trials, patients with high abiraterone C _min had a longer time to PSA progression (PSA doubling time). For a long time, this predicted an extension of overall survival. In addition, patients with low steady-state C _min showed a high incidence of negative PSA attenuation effect (acceleration of PSA doubling time). For example, steady-state C _min of 0-11 ng / mL or 12-35 ng / mL was associated with accelerated PSA doubling time in 24% or 22% of patients, respectively. In contrast, no acceleration of PSA doubling time was observed in any patient with steady-state C _min of abiraterone above 35 ng / mL. However, in the COU-AA-301 and COU-AA-302 Phase 3 trials, only 5% of patients receiving ZYTIGA® reached steady-state C _min of abiraterone above 35 ng / mL. In an FDA regulatory review analysis of COU-AA-301 clinical trial data, subjects in the high abiraterone C _min group tended to prolong overall survival. These results suggest that increasing C _min levels by increasing total abiraterone exposure may improve clinical outcomes with abiraterone. Therefore, in some practices, the pharmaceutical formulations of the present disclosure are, in human patients, greater than 12 ng / mL, greater than 20 ng / mL, greater than 30 ng / mL, greater than 40 ng / mL, greater than 50 ng / mL, greater than 60 ng / mL, More than 70 ng / mL, more than 80 ng / mL, more than 90 ng / mL, or more, or more than about 12 ng / mL, more than about 20 ng / mL, more than about 30 ng / mL, more than about 40 ng / mL, about 50 ng / mL Super, over 60 ng / mL, over 70 ng / mL, over 80 ng / mL, over 90 ng / mL, or more, or up to 100 ng / mL, or up to about 100 ng / mL C _min May contain a sufficient amount of amorphous avilateron or a salt thereof. In some practices, the pharmaceutical formulations of the present disclosure are greater than 12 ng / mL, greater than 20 ng / mL, greater than 20 ng / mL, greater than 25 ng / mL, greater than 30 ng / mL, greater than 35 ng / mL, in a population of human patients. Over 40 ng / mL, over 45 ng / mL, over 50 ng / mL, over 55 ng / mL, over 60 ng / mL, over 65 ng / mL, over 70 ng / mL, over 75 ng / mL, over 80 ng / mL, over 85 ng / mL, More than 90 ng / mL, more than 95 ng / mL, or more, or more than about 12 ng / mL, more than about 20 ng / mL, more than about 20 ng / mL, more than about 25 ng / mL, more than about 30 ng / mL, about 35 ng / Over mL, over 40 ng / mL, over 45 ng / mL, over 50 ng / mL, over 55 ng / mL, over 60 ng / mL, over 65 ng / mL, over 70 ng / mL, over 75 ng / mL, To reach geometric average C _min up to about 80 ng / mL, about 85 ng / mL, about 90 ng / mL, about 95 ng / mL, or more, or up to 100 ng / mL, or up to about 100 ng / mL. May contain a sufficient amount of amorphous avilateron or a salt thereof.

In another study (clinicaltrials.gov: NCT01637402), plasma of patients receiving 1,000 mg / day abiraterone acetate, which did not show PSA reduction after 12 weeks of treatment, called "primary resistance" to abiraterone acetate therapy. Medium abiraterone levels were lower than in patients who showed decreased PSA after 12 weeks of therapy called "responders." Plasma avilateron levels in primary tolerant patients were also significantly lower compared to responders during disease progression during standard dose therapy (1,000 mg / day). Therefore, the term "tolerance" as used herein in connection with abiraterone acetate therapy refers to patients who have never been observed to have therapeutic efficacy such as decreased PSA in response to abiraterone acetate, eg, ZYTIGA®. May point to. In contrast, the term "responsive" as used herein in connection with abiraterone acetate therapy has been observed to have therapeutic efficacy such as decreased PSA in response to abiraterone acetate, eg ZYTIGA®. May refer to a patient. In addition, the term "acquired resistance" as used herein is used as compared to pretreatment levels after treatment with abiraterone acetate, eg, ZYTIGA®, over a period of time (eg, at least 12 weeks). Refers to patients who have previously shown a decrease in PSA, eg, a decrease in PSA up to 50%, or greater than 50%, but no longer respond to therapy as indicated by an increase in PSA.

These results suggest that increasing plasma abiraterone levels may improve clinical outcomes with abiraterone. Therefore, administration of the pharmaceutical formulations of the present disclosure may result in increased plasma avilateron levels in patients. Administration of the pharmaceutical formulations of the present disclosure may be associated with decreased tolerance and / or increased response to administered abiraterone, for example, a greater proportion of patients may have decreased PSA levels or prolonged progression-free periods. For example, more parts of the patient may show an increase in the time to increase PSA levels and / or an improvement in one or more other clinical endpoints of disease progression. Administration of the pharmaceutical formulations of the present disclosure increases plasma abiraterone levels in patients who have previously shown resistance to abiraterone acetate, eg, ZYTIGA® therapy, eg, primary or acquired resistance. May bring. Administration of the pharmaceutical formulations of the present disclosure may result in increased plasma abiraterone levels in patients who were previously responsive to abiraterone acetate, eg, ZYTIGA® therapy.

When patients were given ZYTIGA® with a high-fat diet, oral exposure was significantly increased, with maximum serum concentration (C _max ) and plasma drug concentration-time curve area (AUC) 17-fold, respectively. And 10 times. Recent studies have shown that this significant dietary effect is due to increased solubility of abiraterone acetate, such as ZYTIGA® and abiraterone, in intestinal juices in the fed state. Due to the magnitude of this diet and the variation in dietary content, ZYTIGA® must be taken on an empty stomach.

To improve the solubility and bioavailability of abiraterone, abiraterone acetate prodrug forms of abiraterone such as ZYTIGA® have been developed. However, the effectiveness of prodrugs for improving bioavailability is limited, as evidenced by the dietary and pharmacokinetic variability cited on the label. In addition, exposure did not increase significantly (8% average AUC increase) when the ZYTIGA® dose was doubled from 1,000 mg to 2,000 mg. In addition, in the NCT01637402 trial, doubling the dose of abiraterone acetate in responder patients after signs of disease progression was not found to have clinical benefit for disease progression. The results of these studies indicate that ZYTIGA® was dosed near the absorption limit. The pharmaceutical formulations of the present disclosure may exhibit an improved therapeutic effect, bioavailability, C _min , or C _max as compared to an equal amount of crystalline abiraterone or an equal amount of crystalline abiraterone acetate, eg, amorphous abiraterone. , May contain active abiraterone.

The pharmaceutical formulations of the present disclosure have greater therapeutic effect, same or greater bioavailability, same or greater than equal doses of crystalline abiraterone acetate, eg ZYTIGA®, administered at the same frequency. A dosage form containing abiraterone in an amount sufficient to achieve a larger C _min , or the same or greater C _max , eg, a unit dosage form, and frequently enough to achieve it. It may be administered.

The pharmaceutical formulations of the present disclosure have a therapeutic effect, bioavailability, C _min , or C that is equal to or greater than that of crystalline abiraterone acetate, eg, ZYTIGA®, administered at 1000 mg once daily on an empty stomach. It may be administered in a dosage form containing a sufficient amount of abiraterone to achieve _max , for example, in a unit dosage form and at a sufficient frequency to achieve it.

For example, the exemplary abiraterone pharmaceutical formulation DST-2970 IR of the present disclosure administered at a 200 mg dose as compared to ZYTIGA® administered at a 1,000 mg dose, as exemplified in Example 16. , Increased plasma abiraterone levels, including increased Cmax and increased AUC _0-t . ZYTIGA® administered to fasted human subjects when the results were adjusted to take into account the dose difference between DST-2970 IR administered at 200 mg and ZYTIGA® administered at 1,000 mg. ), The exemplary formulation DST-2970 IR increased Cmax by more than 6-fold and AUC _0-t by more than 3-fold in fasted human subjects.

Thus, in some practices, administration of the pharmaceutical formulations of the present disclosure, eg, in unit dosage form, as compared to administration of an equal amount of crystalline abiraterone or crystalline abiraterone acetate, eg ZYTIGA®. Cmax is more than 1.5 times, more than 2 times, more than 3 times, more than 4 times, more than 5 times, more than 6 times, more than 7 times, more than 8 times, more than 9 times, more than 10 times, or 20 times in human patients. May be super or more.

Thus, in some practices, administration of the pharmaceutical formulations of the present disclosure, eg, in unit dosage form, as compared to administration of an equal amount of crystalline abiraterone or crystalline abiraterone acetate, eg ZYTIGA®. AUC _0-t in human patients more than 1.5 times, more than 2 times, more than 3 times, more than 4 times, more than 5 times, more than 6 times, more than 7 times, more than 8 times, more than 9 times, or more than 10 times , Or more.

After many days of ZYTIGA® at 1,000 mg daily, mCRPC patients showed 79% variability for C _max and 64% for AUC _0-24h . Administration of the pharmaceutical formulations of the present disclosure, eg, in unit dosage form, as compared to administration of an equal dose of crystalline abiraterone or crystalline abiraterone acetate, eg ZYTIGA®, has two standard deviations in mean response. At least 5% reduction, at least 10% reduction, at least 20% reduction, at least 30% reduction, at least 40% reduction, at least 5% reduction in therapeutic effect, bioavailability, C _min , or C _max variation among patients with a response within. It may result in a 50% reduction, at least 60% reduction, at least 70% reduction, at least 80% reduction, or at least 90% reduction.

For example, as exemplified in Example 28, the pharmaceutical formulations of the present disclosure containing up to 30% by weight of abiraterone can be an equal or greater amount of crystalline abiraterone or crystalline abiraterone acetate, eg, Zytiga (registered). It may result in lower drug exposure variability (eg, lower% CV for AUC _(0-48hr)) compared to administration of the trademark).

For example, as exemplified in Example 16, the exemplary Avilateron pharmaceuticals of the present disclosure administered at a dose of 200 mg to a fasted human subject as compared to a fasted human subject to which 1,000 mg of ZYTIGA® was administered. DST-2970 IR reduced the variability of the geometric mean of C _max by 6% and the variability of the geometric mean of AUC _0-t by 4%. In addition, C _max by the exemplary Avilateron pharmaceutical formulation DST-2970 IR of the present disclosure administered at a dose of 200 mg to a feeding human subject as compared to a fasting human subject receiving 1,000 mg of ZYTIGA®. The variability of the geometric mean of AUC 0-t was reduced by 25% and the variability of the geometric mean of AUC _0-t was reduced by 23%.

Administration of ZYTIGA® with a high-fat diet increased the geometric mean of C _max by 17-fold and AUC _0-∞ by 10-fold. The therapeutic effect, bioavailability, administration of the pharmaceutical formulations of the present disclosure, eg, in unit dosage form, as compared to the administration of equal doses of crystalline abiraterone or crystalline abiraterone acetate, eg ZYTIGA®. C _min , or C _max fasting vs. high fat diet variation at least 10% reduction, at least 20% reduction, at least 30% reduction, at least 40% reduction, at least 50% reduction, at least 60% reduction, at least 70% reduction, May result in at least 80% reduction, or at least 90% reduction.

For example, as illustrated in Example 16, a human feeding 200 mg of the exemplary abiraterone pharmaceutical formulation DST-2970 IR of the present disclosure compared to administration of 200 mg DST-2970 IR to a fasting human subject. When administered to subjects, C _max was slightly (about 30%) reduced and AUC _0-t was slightly reduced.

Thus, in some practices, administration of the pharmaceutical formulations of the present disclosure, eg, in unit dosage form, when administered in a fasting state as compared to when administered in a fasting state, is C _max or AUC _0-t may result in fluctuations of less than 50%, less than 40%, less than 30%, less than 20%, less than 10%, or less than 5%, or less than 2%, eg, increase or decrease.

The above and other improvements are present in the pharmaceutical formulations of the present disclosure, at least in part, as compared to the solubility of crystalline abiraterone or crystalline abiraterone acetate, eg, ZYTIGA®, in other formulations. It may be due to the improvement of abiraterone solubility when it is used.

Abiraterone is typically co-administered with a glucocorticoid replacement API, such as prednisone, methylprednisone, or prednisolone. For example, abiraterone acetate, such as ZYTIGA®, is typically co-administered twice daily with a dose of 5 mg of prednisone, methylprednisone, or prednisolone. Methyprednisolone and dexamethasone may also be suitable glucocorticoid replacement APIs, with similar doses calculated to achieve a glucocorticoid replacement effect similar to prednisone, methylprednisone, or prednisolone, especially 5 mg. It may be given with prednisone, methylprednisone, or prednisolone twice daily.

Abiraterone is an active metabolite of abiraterone acetate and is expected to have the same or similar biological effects as abiraterone acetate such as ZYTIGA® and is therefore administered with a glucocorticoid replacement API in a similar dosing regimen. Can be done.

The pharmaceutical formulations of the present disclosure may further comprise a glucocorticoid supplement API, such as prednisone, methylprednisolone, prednisolone, methylprednisolone, or dexamethasone, or other alkylated forms, along with abiraterone and excipients.

The pharmaceutical formulations of the present disclosure have a therapeutic effect equal to or greater than 1000 mg of amorphous abiraterone, or 1000 mg of crystalline abiraterone or crystalline abiraterone acetate when ingested on an empty stomach, eg, ZYTIGA®. , Bioavailability, C _min , or C _max may be contained in sufficient amounts of amorphous abiraterone in the patient. Such formulations may be designed for once-daily administration. Administration may be combined with a glucocorticoid replacement API, eg, prednisone, methylprednisolone, prednisolone, methylprednisolone, or dexamethasone, eg, co-administered twice daily.

The pharmaceutical formulations of the present disclosure have a therapeutic effect equal to or greater than 1000 mg of amorphous abiraterone, or 1000 mg of crystalline abiraterone or crystalline abiraterone acetate when ingested on an empty stomach, eg, ZYTIGA®. , Bioavailability, C _min , or C _max in a patient with sufficient amount of amorphous abiraterone, eg, 5 mg dose of glucocorticoid supplement API, eg, prednisone, methylprednisolone, prednisolone, methylprednisolone, or dexamethasone. May be included with. Such formulations are, for example, in doses of 5 mg and for once-daily administration in combination with a once-daily glucocorticoid replacement API, such as co-administration of prednisone, methylprednisolone, prednisolone, methylprednisolone, or dexamethasone. It may be designed.

The pharmaceutical formulations of the present disclosure have the same or greater therapeutic effect on 500 mg of amorphous abiraterone, or 500 mg of crystalline abiraterone or crystalline abiraterone acetate when ingested on an empty stomach, eg, ZYTIGA®. , Bioavailability, C _min , or C _max may be contained in sufficient amounts of amorphous abiraterone in the patient. Such formulations may be designed for twice-daily administration or two unit dosage forms may be designed to be administered once-daily. Administration may be combined with, for example, a 5 mg dose, eg, a twice-daily glucocorticoid replacement API, eg, co-administration of prednisone, methylprednisolone, prednisolone, methylprednisolone, or dexamethasone.

The pharmaceutical formulations of the present disclosure have a therapeutic effect equal to or greater than 500 mg of amorphous abiraterone, or 500 mg of crystalline abiraterone or crystalline abiraterone acetate when ingested on an empty stomach, eg, ZYTIGA®. , Bioavailability, C _min , or C _max in a patient with sufficient amount of amorphous abiraterone, eg, 2.5 mg dose of glucocorticoid supplement API, eg, prednisone, methylprednisolone, prednisolone, methylprednisolone, or It may be included with dexamethasone. Such formulations may be designed for twice-daily administration. Such formulations may be combined with, for example, a 5 mg dose and a once-daily glucocorticoid replacement API, eg, co-administration of prednisone, methylprednisolone, prednisolone, methylprednisolone, or dexamethasone.

The pharmaceutical formulations of the present disclosure have a therapeutic effect equal to or greater than 250 mg of amorphous abiraterone, or 250 mg of crystalline abiraterone or crystalline abiraterone acetate when ingested on an empty stomach, eg, ZYTIGA®. , Bioavailability, C _min , or C _max may be contained in sufficient amounts of amorphous abiraterone in the patient. Such formulations may be designed to administer two unit dosage forms twice daily or four unit dosage forms once daily. Administration may be combined with, for example, a 5 mg dose, eg, a twice-daily glucocorticoid replacement API, eg, co-administration of prednisone, methylprednisolone, prednisolone, methylprednisolone, or dexamethasone.

The pharmaceutical formulations of the present disclosure are 1000 mg, 500 mg, 250 mg, 200 mg, 150 mg, 100 mg, 70 mg, 50 mg, 25 mg, or 10 mg of amorphous abiraterone, including the range of 10 mg to 70 mg, 25 mg to 70 mg, or 50 mg to 70 mg. Or 1000, 500 mg, 250 mg, 200 mg, 150 mg, 100 mg, 50 mg, or 25 mg of crystalline abiraterone or crystalline abiraterone acetate, eg, ZYTIGA® or greater treatment when taken on an empty stomach. An amount of amorphous abiraterone sufficient to achieve efficacy, bioavailability, C _min , or C _max in a patient, eg, 1.25 mg dose of glucocorticoid supplement API, eg prednisone, methylprednisolone, prednisolone, methylprednisolone, Alternatively, it may be included with dexamethasone. Such formulations may be designed for once-daily administration. Such formulations may be designed for twice-daily administration. Such formulations may be designed for administration three times daily, four times daily, or even more. Such formulations may be combined with, for example, a 5 mg dose and a once-daily glucocorticoid replacement API, eg, co-administration of prednisone, methylprednisolone, prednisolone, methylprednisolone, or dexamethasone.

Variations on the above-mentioned example formulations and administration plans are possible. For example, the amount of abiraterone, the glucocorticoid replacement API, or both in the pharmaceutical formulation can be varied based on the intended dosing regimen.

Prednisone, methylprednisolone, prednisolone, methylprednisolone, or dexamethasone and its alkylated forms are listed as specific glucocorticoid supplement APIs, but other glucocorticoid supplement APIs may also be used. A combination of glucocorticoid APIs may be used in co-administered pharmaceutical formulations.

In general, the pharmaceutical formulations of the present disclosure can be used to administer any amount of abiraterone to a patient on any schedule.

The pharmaceutical formulations of the present disclosure can be used to administer a certain amount of abiraterone to a patient on a variable schedule. For example, such a modifiable schedule could be, for example, over a 28-day period, with daily dosing frequency, eg, once daily (QD), twice daily (BID), on each of the 28 days of the period. , 3 times a day (TID), and 4 times a day (QID) may include, but are not limited to. For example, such a modifiable schedule may be a combination of different doses on different days within a 28-day period, eg, any of the doses disclosed herein, eg, 1-3 days of a 28-day period. The eyes may contain 250 mg abiraterone / day, 3 times daily, followed by 100 mg / day, once daily on days 4-28, but are not limited to this. Other combinations of daily dosing frequency and daily dose can be identified by one of ordinary skill in the art by reading this disclosure.

In addition, any pharmaceutical product of the present disclosure may be co-administered with or without the pharmaceutical product, along with any other API that also treats prostate cancer, abiraterone side effects, or prostate cancer side effects. can. Co-administered APIs include glucocorticoid replacement APIs or other APIs for treating prostate cancer, such as APIs used in androgen ablation therapy, non-steroidal androgen receptor inhibitors, taxans, gonad stimulating hormone-releasing hormones. Antagonists, gonad stimulating hormone-releasing hormone analogs, androgen receptor antagonists, non-steroidal anti-androgen, luteinizing hormone-releasing hormone analogs, anthracendion antibiotics, and radiopharmaceuticals, and any combination thereof, such as bicalutamide, eg. CASODEX® (Astra Zenica, North Carolina, US), Kabazitaxel, eg JEVTANA® (Sanofi-Aventis, France), Degalerix, Docetaxel, eg TAXOTERE® (Sanofi-Aventis), Enzalutamide, For example, XTANDI® (Astellas Pharma, Japan), flutamide, goserelin acetate, eg ZOLADEX® (TerSera Therapeutics, Iowa, US), leuprorelin acetate, eg LUPRON® (Abbvie, Illinois, US), LUPRON® DEPOT (Abbive), LUPRON® DEPOT-PED (Abbive), and VIADUR® (ALZA Corporation, California, US), mitoxanthron hydrochloride, nitamide, eg NILANDRON (Registered Trademarks) (Concordia Pharmaceuticals, Barbados), and radium dichloride 223, such as XOFIGO® (Bayer Healthcare Pharmaceuticals, New Jersey, US), and any combination thereof may be included.

The amorphous abiraterone in the pharmaceutical formulation of the present disclosure can be administered in tablets or capsules that are less than possible or smaller than possible with the formulation crystalline abiraterone acetate, eg ZYTIGA®. This increases patient compliance and reduces patient discomfort.

The pharmaceutical formulations of the present disclosure may be particularly useful when the patient has experienced a suboptimal response to a formulation containing crystalline abiraterone acetate, such as ZYTIGA®.

The pharmaceutical formulations of the present disclosure may be useful in patients who have previously demonstrated resistance to formulations containing crystalline abiraterone acetate, such as ZYTIGA®.

The pharmaceutical formulations of the present disclosure may be useful in patients who have previously demonstrated responsiveness to formulations containing crystalline abiraterone acetate, such as ZYTIGA®.

The pharmaceutical formulations of the present disclosure include patients with prostate cancer, such as castration-resistant prostate cancer, metastatic cast-resistant prostate cancer, metastatic prostate cancer, locally advanced prostate cancer, recurrent prostate cancer, or other high. It may be given to patients with risk prostate cancer.

The pharmaceutical formulations of the present disclosure may be administered to patients with prostate cancer who have previously been treated with chemotherapy such as docetaxel.

The pharmaceutical formulations of the present disclosure may be administered to patients with prostate cancer who have previously been treated with enzalutamide.

The pharmaceutical formulations of the present disclosure may be administered to a patient in combination with androgen deprivation therapy.

The pharmaceutical formulations of the present disclosure may be administered to patients with breast cancer.

The pharmaceutical formulations of the present disclosure may be administered to breast cancer patients who have previously been treated with chemotherapy such as docetaxel.

The pharmaceutical formulations of the present disclosure may be administered to breast cancer patients who have previously been treated with enzalutamide.

The pharmaceutical formulations of the present disclosure may be administered to a patient in combination with androgen deprivation therapy.

The pharmaceutical formulations of the present disclosure may be administered to patients with salivary gland cancer.

The pharmaceutical formulations of the present disclosure may be administered to patients with salivary gland cancer who have previously been treated with chemotherapy such as docetaxel.

The pharmaceutical formulations of the present disclosure may be administered to patients with salivary gland cancer who have previously been treated with enzalutamide.

The pharmaceutical formulations of the present disclosure may be administered to a patient in combination with androgen deprivation therapy.

The pharmaceutical formulations of the present disclosure may be administered to a patient with cancer known to respond to androgen deprivation therapy.

The pharmaceutical formulations of the present disclosure may be administered to patients with cancer who have previously been treated with chemotherapy such as docetaxel and are known to respond to androgen deprivation therapy.

The pharmaceutical formulations of the present disclosure may be administered to patients with cancer who have previously been treated with enzalutamide and are known to respond to androgen deprivation therapy.

The pharmaceutical formulations of the present disclosure may be administered to a patient in combination with additional androgen deprivation therapy.

Both pharmaceutical formulations may be administered in the form of one or more tablets.

D. Examples This example is provided for illustrative purposes only. This example is not intended to cover the entire scope of the present disclosure and should not be construed as including the entire scope of the present disclosure.

In the present application, various compositions and instruments are identified by trade names. All such trade names are present at the time of the earliest filing date of the present application or at the end of the commercial sale of the product under such trade names, whichever is later. Refers to the relevant composition or instrument of. Those skilled in the art will appreciate that, at different times, different compositions and instruments sold under such trade names are also generally suitable for the same application.

Example 1: Solid Dispersion of Avilateron Containing Various Polymer Appliances Some of which are amorphous solid dispersions, some of which (under the treatment conditions considered) are non-amorphous solid dispersions. , Prepared via thermodynamic formulation using a lab-scale thermokinetic compounder (DisperSol Technologies LLC, Amorphous, Texas). 10 wt% pure crystalline abiraterone was placed in a bag of 90 wt% polymer excipient and polyethylene and physically mixed by hand mixing for 2 minutes. The polymer excipients were different as shown in Table 1. The two-component mixture was then thermodynamically compounded at an injection temperature of 120 ° C to 230 ° C. During the thermodynamic formulation, the material was subjected to a range of shear stresses controlled by a computer algorithm at a specified rotational speed. Once the injection temperature was reached, the resulting thermodynamically treated solid dispersion (KSD) was automatically discharged into a catch tray and immediately quenched between the two stainless steel plates. The thermodynamic formulation outcomes are further listed in Table 1.

(Table 1) Abiraterone-polymer excipient solid dispersion and thermodynamic compounding results

KSD was further crushed into powder using a lab-scale rotor mill (IKA mill, IKA Works GmbH & Co. KG, Staufen, Germany) equipped with a 20 ml crushing chamber and operated at 10000 rpm to 24000 rpm for 60 seconds at a time. .. The ground KSD was sifted and a particle size fraction of ≤250 μm was used for further analysis.

The crystalline properties of pure crystalline avilateron and KSD were analyzed by XRD using a Rigaku MiniFlex 600 benchtop X-ray diffractometer (Rigaku, Inc., Tokyo, Japan). The sample was loaded into an aluminum pan, smoothed with a glass slide, and analyzed in the 2θ range of 2.5 ° to 40.0 ° while rotating. The step size was 0.02 ° and the scanning rate was set to 5.0 ° / min. The following additional instrument settings were used: Slit Condition: Variable + Fixed Slit System; Solar (inc.): 5.0 °; IHS: 10.0mm; DS: 0.625 °; SS: 8.0mm; Solar (rec.) : 5.0 °; RS: 13.0mm (open); monochromatization: kb filter (x2); voltage: 40kV; current: 15mA.

XRD diffraction patterns of pure crystalline abiraterone and various KSDs are shown in FIGS. 1 and 2.

Pure crystalline abiraterone could be treated by thermodynamic formulation with all three common types of polymer excipients tested. Comparing the X-ray diffractogram of pure crystalline Avilateron (Fig. 1) with the X-ray diffractogram of KSD (Fig. 2), the cellulose-based polymer excipient group, hydroxypropylmethyl cellulose with different viscosities, produced amorphous solid dispersion. On the other hand, it can be seen that hydroxypropylmethylcellulose acetate succinate produced KSD with a significantly reduced crystallinity. Within the polyvinyl-based polymer excipient group, polyvinylpyrrolidone and polyvinylacetate phthalate produced amorphous solid dispersion, whereas polyvinyl alcohol 4-88 produced KSD with significantly reduced crystallinity. Polymer excipients based on methacrylic acid-ethyl acrylate copolymers resulted in amorphous solid dispersion.

Example 2: Solid dispersion of abiraterone and various cyclic oligomer excipients Various KSDs of abiraterone and cyclic oligomer excipients were prepared as in Example 1. Table 2 shows the results of thermodynamic compounding with the cyclic oligomer excipient.

(Table 2) Abiraterone-Cyclic oligomer excipient solid dispersion and thermodynamic compounding results

Pure crystalline abiraterone could be treated by thermodynamic formulation with hydroxypropyl β cyclodextrin. The binary mixture of pure crystalline abiraterone and all other cyclodextrins tested remained untreated (under the treatment conditions considered) because there was not enough friction to obtain the injection temperature. The treated mixture was analyzed by XRD as described in Example 1 above. From the resulting X-ray diffraction pattern shown in FIG. 3, it was confirmed that the amorphous solid dispersion was formed. It is expected that other cyclodextrins tested may be treatable if they are pretreated by granulation or slugging and sufficient friction occurs during the thermodynamic formulation. Alternatively, treating these mixtures with a production-scale thermodynamic compound may produce sufficient friction and shear forces, resulting in amorphous compositions that were not possible with research-scale machines.

Example 3: Dissolution Test of Avilaterone Pharmaceutical Formulation The dissolution performance of various pharmaceutical formulations of abiraterone or pure crystalline abiraterone was analyzed using a supersaturated non-sync biphasic dissolution test. A sample corresponding to 31 mg of pure crystalline abiraterone was filled in an elution vessel containing 35 ml of 0.01N HCl and placed in an incubator shaker set to a rotation speed of 37 ° C. and 180 rpm. After 30 minutes, 35 ml of fasting simulated intestinal juice (FaSSIF) was added to the elution vessel. At a predetermined point in time, the sample was withdrawn from the elution vessel and centrifuged using an ultracentrifuge. The supernatant was further diluted with a diluent and analyzed by HPLC. The results are shown in Fig. 4.

Almost all of the pharmaceutical formulations tested for abiraterone and polymer or cyclic oligomeric excipients showed faster elution rates and greater elution degrees compared to pure crystalline abiraterone. Among the amorphous pharmaceutical formulations, those containing hydroxypropyl β-cyclodextrin excipient showed a significantly larger degree of elution as compared with pharmaceutical formulations containing polymer excipients. This result was quite unexpected, as polymers are quite often superior to all other excipients in terms of elution performance in ASD formulations. Therefore, it would not be expected that non-polymers, in this case cyclic oligomers, would certainly provide excellent abiraterone elution performance to the extent shown in FIG.

Example 4: Dissolution Test of Avilaterone Pharmaceutical Formulation Containing Secondary Excipient The hydroxypropyl β-cyclodextrin excipient enhanced the avilateron elution in the acidic phase of the elution test, whereas in the neutral phase, the avilateron Precipitated due to its weak basicity and fairly poor solubility in the non-ionized state. Therefore, it was hypothesized that the addition of a secondary excipient to the formulation slows the precipitation rate in the neutral phase and thus can greatly enhance the total solubility.

Amorphous solid dispersions of 10 wt% avilateron and 90 wt% hydroxypropyl β-cyclodextrin were prepared and sampled to screen for secondary polymer excipients that potentially improve avilateron elution in the neutral phase. An elution medium containing 35 mg of various secondary polymers was used for the acidic phase of the elution test. Figure 5 shows the results of these experiments. All secondary polymer excipients have a slight adverse effect on acidic phase elution, resulting in less than 20% reduction in the area under the elution curve of the associated sample compared to samples without polymer secondary excipients. bottom. In the neutral phase of the elution test, sodium carboxymethyl cellulose, polyvinyl acetate phthalate, and hydroxypropylmethyl cellulose acetate succinate with 5-9% acetate substitution and 14-18% succinate substitution all adversely affected elution. .. However, all remaining secondary excipients showed positive effects, with hydroxypropylmethylcellulose acetate succinates having 10-14% acetate substitutions and 4-8% succinate substitutions showing the best effects. This secondary polymer excipient increased the area under the elution curve 2.4-fold during the neutral phase compared to the sample without the polymer secondary excipient.

Example 5: Optimizing the weight ratio of avilateron, cyclic oligomer excipients, and secondary excipients in an amorphous solid dispersion Concentration of hydroxypropyl β cyclodextrin primary excipient and 10-14% acetate substitution And the concentration of hydroxypropylmethylcellulose acetate succinate secondary excipient with 4-8% succinate substitution was optimized by subjecting the various mixtures to the thermodynamic formulation. Various KSDs of abiraterone and hydroxypropyl β-cyclodextrin primary excipients and various polymer secondary excipients were prepared as in Example 1. Relative weight percent, excipients, and thermodynamic formulation results are listed in Table 3.

(Table 3) Abiraterone-Solid dispersion of primary and secondary excipients and thermodynamic compounding results

All three component mixtures could be treated by thermodynamic formulation. XRD revealed that Example 3.1, which contained only 50% of the primary excipient, did not form an amorphous solid dispersion under the conditions sought (Fig. 6). The other mixture formed an amorphous solid dispersion (Fig. 6).

Performance Evaluation of All Pharmaceutical Compositions Containing Amorphous Avilateron, Hydroxypropyl β Cyclodextrin, and Hydroxypropyl Methyl Cellulose Acetate Succinate with 10-14% Acetate Substitution and 4-8% Succinate Substitution Examples 3 and 4 The dissolution test was performed in the same manner as in. The results are shown in Fig. 7.

In the acidic elution phase, the pharmaceutical formulation of Example 2.4 performed better than all other compositions evaluated (Fig. 7A). However, in the neutral phase, Example 3.4 performed better than the other compositions (Fig. 7B). Similarly, the total elution performance of Example 3.4 was good as compared to the other compositions.

From the results of FIGS. 7A and 7B, it can be expected that the elution enhancement will be better as the relative amount of the polymer secondary excipient in the amorphous solid dispersion increases, based on the initial test of Example 4, but the polymer secondary It can also be seen that as the relative amount of the excipient increases, the relative amount of the cyclic oligomer primary excipient decreases. As a result, the molar ratio of abiraterone: cyclic oligomer excipient, which affects elution performance, is disturbed.

When the active amorphous avirateron and hydroxypropyl β cyclodextrin excipients are present in the amorphous solid dispersion in a weight ratio of 1: 9, the molar ratio is 1: 2.25. When the weight ratio decreases to 1: 8, the molar ratio decreases to 1: 2. Up to this point, optimal elution is still observed. However, it seems that elution enhancement may begin to decline as the molar ratio drops below 1: 2.

Example 6: Supersaturation test using hydroxypropylmethylcellulose acetate succinate ASD with avilateron-hydroxypropyl β-cyclodextrin-10-14% acetate substitution and 4-8% succinate substitution Conventionally, non-sync biphasic dissolution test The pharmaceutical product is expected to reach some degree of supersaturation for the API dissolved in the elution medium. At the supersaturation point, the concentration of API dissolved in the elution medium does not increase any more even if more pharmaceutical preparations are added to the elution medium. This is considered to be the supersaturation threshold, that is, the maximum amount of API that dissolves in the elution medium containing the product. To investigate this phenomenon and to determine the hypersaturation threshold of the avilateron pharmaceutical formulations of the present disclosure, the formulations of Example 3.4 (cyclic oligomer primary excipient and polymer secondary excipient) and Example 1.2 (polymer excipient). Was tested in various amounts. More specifically, with abiraterone levels of 200X (about 62 mg abiraterone), 100X (about 31 mg abiraterone), and 25X (about 7.7 mg abiraterone) compared to the inherent abiraterone solubility in the FaSSIF medium. Preparation was prepared. The dissolution test was performed as in Example 3. The results are shown in Fig. 8.

In the case of the pharmaceutical formulation of Example 3.4, the concentration of abiraterone dissolved in the elution medium in the acidic phase and the neutral phase increased significantly as the initial loading amount of the composition increased from 25X to 100X and further to 200X. .. Conversely, when the pharmaceutical product of Example 1.2 was evaluated at the levels of 25X and 100X, it was observed that the concentration of abiraterone dissolved in the elution medium increased only slightly. From these results, the amorphous solid dispersion containing avilateron, cyclic oligomer primary excipient and polymer secondary excipient is significantly enhanced elution compared to the amorphous solid dispersion containing polymer primary excipient. It has been proven that it can result in a large hypersaturation threshold.

The pharmaceutical product of the present disclosure is at least 100 times, at least 200 times, at least 500 times the concentration of pure crystalline abiraterone when 31 mg of active abiraterone in the pharmaceutical product is added to 35 mL or 0.01N HCl. Or it can be at least 700 times higher.

Example 7: Abiraterone-hydroxypropyl β-cyclodextrin pharmaceutical formulation with increased abiraterone loading by thermodynamic formulation of abiraterone with hydroxypropyl β-cyclodextrin in weight ratios of 1: 9, 1: 4, and 3: 7. It was treated and pulverized according to the method described in Example 1. The details of the formulation and the thermodynamic compounding results are shown in Table 4.

(Table 4) Results of solid dispersion and thermodynamic compounding of abiraterone-hydroxypropyl β-cyclodextrin with various drug loading amounts

The treated pharmaceutical products were analyzed by XRD by the method described in Example 1. From the resulting X-ray diffraction pattern shown in FIG. 9, it was confirmed that the amorphous solid dispersion was formed.

The pharmaceutical product was then subjected to a dissolution test according to the method of Example 3. These results are shown in FIG. From the elution results of all the formulations, it can be seen that the solubility and elution characteristics were significantly enhanced as compared with crystalline abiraterone. However, it was confirmed that the degree of supersaturation depends on the ratio of abiraterone: hydroxypropyl β-cyclodextrin, and that the smaller the ratio, the greater the elution and solubility enhancement. The observation that a weight ratio of 1: 9 gave the best results in this dissolution test was discussed from Example 5 and the preferred molar ratio of abiraterone: hydroxypropyl β cyclodextrin was greater than about 1: 2 or It supports the conclusion that it is equal to this.

Example 8: Solid dispersion of abiraterone acetate and various polymer excipients Abiraterone acetate was treated with various polymers at a 1: 9 weight ratio by thermodynamic formulation and ground according to the method described in Example 1. The details of the formulation and the thermodynamic compounding results are shown in Table 5.

(Table 5) Abiraterone acetate-polymer excipient solid dispersion and thermodynamic compounding results

Bulk abiraterone acetate and the treated formulation were analyzed by XRD according to the method described in Example 1. The X-ray diffraction patterns resulting from the drug substance and the treated formulation are shown in FIGS. 11 and 12, respectively. From the results shown in FIG. 12, it was confirmed that the amorphous solid dispersion of abiraterone acetate and various polymers was formed by thermodynamic compounding.

Then, according to the method of Example 3, the abiraterone acetate-polymer amorphous dispersion was subjected to an elution test in comparison with pure abiraterone acetate. These results are shown in FIG. The elution results demonstrated that the rate and degree of abiraterone acetate was improved compared to the pure drug. However, these elution results are inferior to the elution results demonstrated by Example 9.1 of FIG.

FIG. 13 is a graph of dissolved avilatelon acetate concentration vs. time (elution profile) for various amorphous solid dispersions of pure crystalline avilatelon acetate, or avilateron acetate and various polymeric excipients.

Example 9: Solid Dispersion of Avilaterone Acetate-Hydroxypropyl β Cyclodextrin Avilateron acetate was treated with hydroxypropyl β cyclodextrin at a 1: 9 weight ratio by thermodynamic formulation and ground according to the method described in Example 1. The details of the formulation and the thermodynamic compounding results are shown in Table 6.

(Table 6) Abiraterone acetate-hydroxypropyl β-cyclodextrin solid dispersion composition and thermodynamic compounding results

Bulk abiraterone acetate and the treated formulation were analyzed by XRD according to the method described in Example 1. The X-ray diffraction patterns resulting from the drug substance and the treated formulation are shown in FIGS. 11 and 14, respectively. From the results shown in FIG. 14, it was confirmed that the amorphous solid dispersion of abiraterone acetate and hydroxypropyl β cyclodextrin was formed by thermodynamic compounding.

Then, according to the method of Example 3, the abiraterone acetate-hydroxypropyl β cyclodextrin amorphous dispersion was subjected to an elution test in comparison with pure abiraterone acetate. These results are shown in FIG. The elution results demonstrated that during the acidic phase of the test for the KSD formulation, the rate and degree of elution of abiraterone acetate was significantly improved compared to the pure drug. A large amount of drug precipitate was observed for the KSD composition during the transition to the neutral phase of the test, but the plateau drug concentration was still superior to the crystalline drug control.

Among the amorphous pharmaceutical formulations of avilateron acetate, those containing hydroxypropyl β-cyclodextrin excipient showed a significantly larger degree of elution compared to pharmaceutical formulations containing polymer excipients. This result was quite unexpected, as polymers are quite often superior to all other excipients in terms of elution performance in ASD formulations. Therefore, it would not be expected that non-polymers, in this case cyclic oligomers, would provide excellent abiraterone elution performance to the extent shown in FIG.

FIG. 15 is a graph of dissolved avilateron acetate concentration vs. time (elution profile) for pure crystalline avirateron acetate and amorphous solid dispersion of avirateron acetate and hydroxypropyl β cyclodextrin.

Example 10: Avilaterone acetate with increased loading Avilateron acetate-hydroxypropyl β cyclodextrin pharmaceutical formulation Avilateron acetate is treated with hydroxypropyl β cyclodextrin at a weight ratio of 1: 9 and 1: 4 by thermodynamic formulation. , Grinded according to the method described in Example 1. The details of the formulation and the thermodynamic compounding results are shown in Table 7.

(Table 7) Results of solid dispersion and thermodynamic compounding of abiraterone acetate-hydroxypropyl β cyclodextrin with various drug loading amounts

The treated pharmaceutical products were analyzed by XRD by the method described in Example 1. From the resulting X-ray diffraction pattern shown in FIG. 16, it was confirmed that the amorphous solid dispersion was formed with a large amount of avilateron acetate loading.

Then, the pharmaceutical product was subjected to an elution test according to the method of Example 3. These results are shown in FIG. From the elution results, it can be seen that the degree of supersaturation depends on the ratio of abiraterone acetate: hydroxypropyl β cyclodextrin, and the smaller this ratio, the greater the elution and solubility enhancement. The observation that the 1: 9 weight ratio gave the best results in this dissolution test is the discussion from Example 5 and the preferred molar ratio of abiraterone / abiraterone acetate: hydroxypropyl β cyclodextrin greater than about 1: 2. It supports the conclusion that it is, or is equivalent to this.

Example 11: Supersaturation test using abiraterone acetate-hydroxypropyl β-cyclodextrin ASD Conventionally, in the non-sync biphasic elution test, the pharmaceutical product is expected to reach a certain degree of supersaturation for the API dissolved in the elution medium. To. At the supersaturation point, the addition of more pharmaceutical formulations to the elution medium does not increase the concentration of API dissolved in the elution medium any further. This is considered to be the supersaturation threshold, that is, the maximum amount of API that dissolves in the elution medium containing the product. To determine the supersaturation threshold of abiraterone acetate-hydroxypropyl β-cyclodextrin (1: 9) ASD in Example 9.1, the pharmaceutical product was tested at a concentration 400-100 times the inherent abiraterone solubility in the FaSSIF medium. The dissolution test was carried out as described in Example 3, and the results are shown in FIG.

For the pharmaceutical formulation of Example 9.1, the concentration of abiraterone in the elution medium in the acidic and neutral phases increased significantly as the initial loading of the composition increased from 100X to 200X, 300X and finally 400X. Was observed to do. These results demonstrate that amorphous solid dispersions containing abiraterone acetate and cyclic oligomeric excipients can result in enhanced elution and significantly improved supersaturation thresholds compared to pure APIs. ..

Example 11: Development of Immediate Release Tablets and Gastro-retentive / Extended Release Tablets Containing ASD of Abiraterone and Hydroxypropyl β Cyclodextrin The final dosage form containing the abiraterone-cyclic oligomer amorphous solid dispersion of the present disclosure. In the design of, it was desired to have tablets with different drug release rates to allow for different pharmacokinetic profiles that may have unique therapeutic benefits. Therefore, immediate release (IR) tablets were developed with gastric retention extended release (XR) tablets. Both Example compositions are shown in Table 8.

(Table 8) Development of immediate release tablets and gastric retention / extended release tablets containing abiraterone-hydroxypropyl β-cyclodextrin amorphous solid dispersion

The compositions shown in Table 8 are blended with abiraterone-hydroxypropyl β cyclodextrin ASD powder in a suitable powder blender with a tableting excipient, followed by a suitable pharmaceutical tablet press. Using, this blend was produced by directly compressing to the desired hardness.

For IR tablets, the external phase is conventional with disintegrating tablets, except for HPMCAS and hydroxypropyl β-cyclodextrin, which are included to promote abiraterone supersaturation, especially in the intestinal tract.

For XR tablets, the external phase contains a functional polymer, polyethylene oxide, and hydroxypropylmethyl cellulose. These polymers promote the swelling of the tablets in the stomach, i.e., (1) to facilitate the retention of the tablets in the stomach, and (2) release the abiraterone solubility-enhanced ASD form. It was incorporated into the external phase as a gelling agent for modification. This tablet design aims to isolate the abiraterone dose in the acidic environment of the stomach where the drug dissolves well and prolong the release of dissolved abiraterone in the intestinal tract so that consistent therapeutic abiraterone exposure can be achieved during the therapy period. And.

Example 12: Dissolution test of tablets produced according to Example 11.
Tablets prepared according to Example 11 were eluting tested to determine the rate of abiraterone release from IR and XR dosage forms. To perform the analysis, a USP apparatus II (paddle) dissolution tester equipped with fiber optic UV spectroscopy for in situ drug concentration measurement was used. 50 mg strength tablets were placed in an elution vessel containing 900 ml 0.01N HCl heated to about 37 ° C. at a paddle stirring rate of 75 RPM. The results of this test are shown in FIG.

The elution results shown in FIG. 19 demonstrated a rapid and complete release of abiraterone from the IR tablets of Example 11.1 and a long-term release of abiraterone over 24 hours for the XR tablets of Example 11.2. When administered to patients, IR tablets are expected to provide rapid and complete absorption and a high C _max : C _min ratio. In contrast, XR tablets provide long-term absorption, resulting in a smaller C _max : C _min ratio compared to IR tablets and current commercial products, namely Zytiga and Yonsa. This reduction in the C _max : C _min ratio may be a therapeutic benefit if maintaining abiraterone levels within the treatable time range is significant for therapeutic outcomes during the treatment period. In these cases, rapid absorption and excretion of the immediate release dosage form is not desirable as the plasma concentration of abiraterone drops below the treatment threshold over a period of time prior to the next dose, which may accelerate disease progression. ..

Example 13: Pharmacokinetic study of tablets prepared according to Example 11 in male Beagle dogs Three-way cross to evaluate the in vivo performance of the IR and XR tablets shown in Example 11. In an overstudy design, tablets (50 mg abiraterone) were orally administered to male beagle dogs with Zytiga (250 mg abiraterone acetate). Test dogs were assigned to the dosing group as shown in Table 9. Animals were given the test article as a single oral dose. The tablets were placed on the back of the tongue and the pharynx was massaged to ease swallowing. Then, 10-25 ml of sterile water was immediately administered by syringe to ensure that the tablets were poured / swallowed into the stomach. The first day of dose administration was designated as the first day of the study. For all dosing events, animals were fasted overnight and fed food 4 hours after dosing (after 4 hours of blood sampling). There was a 7-day washout period between dosing events.

(Table 9) Test parameters for pharmacokinetic evaluation of abiraterone tablets in male beagle dogs

Pharmacokinetic (PK) analysis was performed comparing IR and XR tablets with Zytiga reference tablets. The PK parameters are shown in Table 10 and the plasma concentration vs. time profile is shown in FIG. PK analysis comparing the Abiraterone IR tablets of Example 11.1 with Zytiga revealed that the geometric mean ratios of dose-normalized AUC _0-8 and C _max were 14.7 and 13.9, respectively. From these values, it can be seen that the total oral exposure to abiraterone after oral administration of abiraterone IR tablets is about 15 times that of Zytiga, and the peak plasma concentration is about 14 times. This result shows that the bioavailability of abiraterone produced by the composition of the present invention is significantly improved as compared with the commercial product Zytiga. To the best of our knowledge, such high plasma concentrations compared to the dose observed using the IR tablets of Example 11.1 have never been previously reported in the literature and therefore this composition. It shows the uniqueness of things.

PK analysis comparing the Abiraterone XR tablets of Example 11.2 with Zytiga revealed that the geometric mean ratios of dose-normalized AUC _0-8 and C _max were 1.8 and 0.79, respectively. From these values, XR tablets almost doubled the total exposure (AUC) while reducing the peak abiraterone plasma concentration (C _max ) compared to Zytiga and thus reducing the C _max to C _min ratio. You can see that. Such results have never been achieved, especially given that abiraterone has shown an excessive solubility problem, especially at neutral pH in the intestinal tract. Such results were achieved only by the unique combination of the novel solubility-enhanced abiraterone-cyclic oligomer ASD and hydrogel matrix of the XR tablets of the present invention. Once again, if consistent, round-the-clock drug levels above the treatment threshold are required to achieve the desired medical outcome, then the drug release profile of abiraterone XR tablets The unique PK profile that is triggered is expected to provide therapeutic benefits.

¹平均体重調節用量
²幾何平均値 (Table 10) Pharmacological overview of abiraterone IR tablets and XR tablets (50 mg abiraterone) vs. Zytiga (250 mg abiraterone acetate) in fasting male beagle dogs after a single oral dose.

¹ Average weight adjustment dose
² Geometric mean

Example 14: Increased systemic concentration caused by abiraterone-cyclic oligomer amorphous solid dispersion enhances tumor regression in xenograft mice To test the hypothesis that increased systemic abiraterone levels improve tumor response. In a 22RV1 human prostate tumor xenograft model, a test was performed to evaluate the efficacy of the composition prepared according to Example 2.4 in comparison with abiraterone acetate. However, an incremental dose PK test was performed in non-tumor SCID mice prior to administration to xenograft mice to create an exposure-dose curve for Example 2.4 composition vs. abiraterone acetate. Based on this curve, doses for xenograft studies were selected according to the observed systemic exposure.

For the PK test, both test articles were dosed by oral gavage as a powder reconstituted in an aqueous suspension vehicle. All animals were fasted overnight before dosing. The test parameters are summarized in Table 11 and the resulting exposure-to-dose curve is shown in Figure 21.

(Table 11) Test parameters from the incremental dose study in SCID mice comparing the pharmacokinetics of Example 2.4 with abiraterone acetate.

The dose-exposure curve shown in FIG. 21 reveals that the dose linearity and total exposure achieved with the Example 2.4 composition are superior to abiraterone acetate. More specifically, the AUC ratios of Example 2.4 and abiraterone acetate at low, medium and high doses were 4.0, 7.23 and 2.6, respectively. A straight trend line was fitted to both exposure-to-dose curves to calculate the appropriate xenograft test dose based on patient exposure data obtained from the Zytiga label. This analysis determined that the low and high doses of abiraterone acetate were 22.4 mg / kg and 100 mg / kg, and the corresponding doses of the Example 2.4 composition were 20 mg / kg and 89.2 mg / kg.

The purpose of the xenograft mouse study was to confirm the antitumor activity of the composition vs. abiraterone acetate prepared according to Example 2.4 as a single agent in a 22RV1 human prostate tumor xenograft model. This study was performed on CB.17 SCID mice injected with 22RV1 cells (5x10 ⁶ cells / mouse) subcutaneously into the right abdomen. Tumors were grown to an average tumor size of 100-150 mm ³ prior to study enrollment. Mice were dosed once daily with the test article and reference by gavage according to Table 12. Tumor volume was measured throughout the study. The study was terminated on day 26, when the mean tumor mass in the two experimental groups reached ≥1500 mm ³ .

(Table 12) Dosing parameters for antitumor study in 22RV1 xenograft mice

The test results are shown in FIG. 22 and Table 13. The results show that at low doses (p = 0.014) and high doses (p <0.001), treatment with the Example 2.4 composition showed a statistically significant reduction in tumor growth compared to vehicle controls. Conversely, treatment with abiraterone acetate did not result in statistically different tumor growth compared to vehicle controls.

(Table 13) Tumor growth results after once-daily administration of abiraterone acetate or the composition from Example 2.4 to 22RV1 xenograft mice at two dose levels.

Prophetic Example 15: Therapeutic Efficacy in Cancers and Other Conditions Responsive to Androgen Suppression From these results in Example 14, systemic abiraterone achieved by the compositions disclosed herein. It was clearly demonstrated that increased concentrations lead to a superior antitumor response compared to abiraterone acetate. The in vivo systemic abiraterone exposure observed after oral administration of the compositions disclosed herein is considered to be the largest published to date. Therefore, we believe that this antitumor response is unprecedented. Estimating this result by applying it to human patients, it is shown that the compositions of the present invention provide excellent therapeutic efficacy in patients with cancers that respond to androgen suppression such as prostate and breast cancer.

For example, also known as the steroid 17α-monooxygenase, 17α-hydroxylase, 17,20-lyase, or 17,20-desmorase, or associated with cytochrome P450 17A1 (CYP17A1) responsive to CYP17A1 inhibitors. It is intended to increase the therapeutic efficacy associated with the pharmaceutical formulations of the present disclosure in steroids and other conditions.

For example, the increased therapeutic efficacy associated with the pharmaceutical formulations of the present disclosure includes cast-resistant prostate cancer, idiopathic prostate cancer, prostate cancer associated with obesity, prostate cancer associated with high plasma levels of testosterone, BRCA1 or BRCA2. Genes, or other prostate cancer-related genes, such as Hereditary Prostate cancer gene 1 (HPC1), androgen receptor gene and vitamin D receptor gene, TMPRSS2-ETS gene family fusion, such as TMPRSS2-ERG or TMPRSS2-ETV1 / 4. Eeles RA, et al. (2008) Nature Genetics. 40 (2008) Nature Genetics. 40 (2008) Nature Genetics. 40 (2008) Nature Genetics. ): 316-321; Thomas G, et al. (2008) Nature Genetics. 40 (3): Includes monobasic polymorphisms (SNPs) identifiable by those of skill in the art, including those described in 310-315. It is intended to be achieved in prostate cancer, but not limited to this.

For example, the increased therapeutic efficacy associated with the pharmaceutical formulations of the present disclosure is intended to be achieved in breast cancers including, but not limited to, triple-negative breast cancer. The diagnosis of "triple-negative breast cancer" is that the three most common types of receptors (estrogen, progesterone, and HER-2 / neu genes) that are known to stimulate most breast cancer growth are cancer tumors. Means that it does not exist in.

For example, increased therapeutic efficacy associated with the pharmaceutical formulations of the present disclosure includes, but is not limited to, estrogen receptor-positive, progesterone receptor-positive, and / or HER-2 receptor-positive breast cancers. It is intended to be accomplished.

For example, the increased therapeutic efficacy associated with the pharmaceutical formulations of the present disclosure may be breast cancer, eg, idiopathic breast cancer, or BRCA1 or BRCA2, p53 (eg, Lee), which can be identified by those skilled in the art by reading this disclosure. Gene mutations associated with, but not limited to, gene mutations in Fraumeni Syndrome), PTEN (eg Cowden Syndrome), STK11 (eg Poitz-Jegers Syndrome Syndrome), CHEK2, ATM, BRIP1 and PALB2. It is intended to be accomplished in the associated breast cancer.

For example, the increased therapeutic efficacy associated with the pharmaceutical formulations of the present disclosure is triple-negative androgen receptor-positive locally advanced / metastatic breast cancer or ER-positive HER2-negative breast cancer, especially those that can be identified by those skilled in the art by reading this disclosure. It is intended to be achieved in other breast cancers, including, but not limited to, ER-positive metastatic breast cancer or apocrine breast cancer.

For example, the increased therapeutic efficacy associated with the pharmaceutical formulations of the present disclosure may be identified by other cancers, eg, those artisan by reading this disclosure, such as Cushing's syndrome and adrenocortical carcinoma, urinary tract epithelial cancer or bladder. It is intended to be accomplished in cancer or bladder tumors, recurrent / metastatic salivary gland cancers that express androgen receptors, or recurrent and / or metastatic salivary gland cancers or salivary gland tumors or salivary gland duct cancers.

Increased therapeutic efficacy associated with the pharmaceutical formulations of the present disclosure are, in particular, acne, seborrhea, androgen-induced hair loss, hirsutism, hidradenitis suppurativa, sexual prematurity in boys, hyperlibido, paraphilia, benign prostate enlargement. (BPH), and hyperandrogenemia in women, including, but not limited to, polycystic ovary syndrome (PCOS), are also intended to be accomplished in non-cancer androgen-dependent conditions.

Example 16: Pharmacokinetic study in human subjects treated with IR abiraterone tablets prepared according to Example 11.1 compared to ZYTIGA®.
Oral administration of 200 mg / day IR abiraterone (also referred to herein as DST-2970 IR) prepared according to Example 11.1 as compared to oral administration of 1,000 mg / day abiraterone acetate (ZYTIGA®). A healthy male human subject (n = 24) was enrolled in a study to evaluate the pharmacokinetics of abiraterone. Subjects were given the following procedures: (1) 200 mg DST-2970 IR, fasting; (2) 200 mg DST-2970 IR, fasting; or (3) 1,000 mg ZYTIGA®, fasting. ..

200 mg / day DST-2970 IR was administered as a 4x50 mg IR tablet and ZYTIGA® was administered as a 2x500 mg film-coated tablet.

The study followed a single-center, randomized, single-dose, laboratory-blinded, 3 period, 6 sequence, crossover design. Subjects were randomized to the treatment sequence as shown in Table 14.

処置-1=A;処置-2=B;処置-3=C (Table 14) Treatment sequence

Action-1 = A; Action-2 = B; Action-3 = C

Between drug administrations, there was a 7-day drug holiday, which was about 12 times the expected half-life of abiraterone.

During each study period, approximately 240 ml of water and abiraterone were administered as a single oral dose in the morning with food or fasted after a 10-hour overnight fast according to the treatment allocation.

During each test period, 21 blood samples were collected for PK evaluation. The first blood sample was collected before drug administration, whereas the other blood samples were collected by 72 hours after drug administration.

Abiraterone plasma levels were measured by a validated bioanalytical method.

Statistical analysis of all PK parameters was based on the ANOVA model. The 90% confidence intervals on both sides of the ratio of geometric least squared mean (LSmeans) are from time 0 to the end using Cmax (maximum observed concentration) and AUC _0-t (linear trapezoidal method). It was obtained from the natural logarithmic conversion (ln conversion) PK parameters including the area under the cumulative concentration-time curve calculated up to the time of the observed quantifiable concentration.

The comparative bioavailability evaluation was carried out as follows. Statistical inference of abiraterone from DST-2970 IR and Zytiga® is based on the following criteria: the difference between treatment -1 and treatment -3 for the ln conversion parameters C _max and AUC _0-t . It was based on a ratio of geometric LSmeans calculated from the exponential of the difference between Treatment-2 and Treatment-3 and a bioequivalence approach with a corresponding 90% confidence interval.

The food efficacy evaluation was carried out as follows. The effect of a high-fat diet on the bioavailability of abiraterone from DST-2970 IR was confirmed by comparing C _max and AUC _0-t obtained after administration of DST-2970 IR under fasting and feeding conditions. rice field.

であった。式中、MSEは、ln変換パラメータのANOVAモデルから得られた平均二乗誤差である。 The formula for estimating the intra-subject coefficient of variation (CV) is:

Met. In the equation, MSE is the mean square error obtained from the ANOVA model of the ln transformation parameter.

Pharmacokinetic parameters for C _max , dose-adjusted C _max , AUC _0-t and dose-adjusted AUC _0-t were calculated. Dose adjustments were obtained by dividing the PK parameters by the abiraterone dose in mg. Zytiga® contains abiraterone acetate, so the amount of abiraterone in 1,000 mg of Zytiga® is 892.3 mg.

Figures 23-27 and Tables 15-18 report test results.

(Table 15) Abiraterone Cmax in human subjects after oral administration of 200 mg abiraterone DST-2970 IR (when fasting or fasting) or 1,000 mg abiraterone acetate ZYTIGA® (fasting).

「F」はバイオアベイラビリティを示す。 (Table 16) Dose-adjusted abiraterone Cmax in human subjects after oral administration of 200 mg abiraterone DST-2970 IR (when fasting or fasting) or 1,000 mg abiraterone acetate ZYTIGA® (fasting)

"F" indicates bioavailability.

(Table 17) Abiraterone AUC _0-t in human subjects after oral administration of 200 mg abiraterone DST-2970 IR (when fasting or fasting) or 1,000 mg abiraterone acetate ZYTIGA® (fasting).

(Table 18) Dose-adjusted abiraterone AUC _0-t in human subjects after oral administration of 200 mg abiraterone DST-2970 IR (when fasting or fasting) or 1,000 mg abiraterone acetate ZYTIGA® (fasting)

The results show that in human subjects, the exemplary abiraterone pharmaceutical formulation DST-2970 IR dose administered at 200 mg increased Cmax and AUC _0-t compared to ZYTIGA® administered at the 1,000 mg dose. It can be seen that it resulted in an increase in plasma abiraterone levels, including an increase in plasma.

Thus, subjects receiving the exemplary abiraterone pharmaceutical formulation DST-2970 IR at approximately 1/5 of the ZYTIGA® dose showed improved absorption and increased abiraterone exposure, which increased therapeutic effect in patients. Is expected to bring.

ZYTIGA® administered to fasted human subjects when the results were adjusted to take into account the dose difference between DST-2970 IR administered at 200 mg and ZYTIGA® administered at 1,000 mg. In comparison, the exemplary formulation DST-2970 IR increased Cmax by more than 6-fold in fasted human subjects.

ZYTIGA® administered to fasted human subjects when the results were adjusted to take into account the dose difference between DST-2970 IR administered at 200 mg and ZYTIGA® administered at 1,000 mg. ), The exemplary formulation DST-2970 IR increased AUC _0-t more than 3-fold in fasted human subjects.

Compared to fasted human subjects receiving 1,000 mg of ZYTIGA®, DST-2970 IR 200 mg reduced the geometric mean variation of C _max by 6% and AUC ₀ when administered to fasted human subjects. It resulted in a 4% reduction in the variability of the geometric mean of _-t . In addition, DST-2970 IR 200 mg reduced the geometric mean variation of C _max by 25% when administered to feeding human subjects compared to fasted human subjects receiving 1,000 mg of ZYTIGA®. , AUC _0-t resulted in a 23% reduction in geometric mean variability.

In addition, administration of the 200 mg DST-2970 IR of the present disclosure to a feeding human subject has a very slight or slight (eg, eg) Cmax compared to administration of 200 mg of DST-2970 IR to a fasting human subject. Approximately 30%) decreased and AUC _0-t decreased or did not decrease very slightly.

Predictive Example 17: Clinical study in patients with metastatic castration-resistant prostate cancer (mCRPC) and primary resistance to abiraterone This example is in patients with metastatic castration-resistant prostate cancer (mCRPC) who have primary resistance to abiraterone. Describes a predictive, multicenter, open-label, dose-escalation study evaluating the safety, tolerability, pharmacokinetics, and anti-prostate-specific antigen (PSA) activity of DST-2970 tablets.

The investigational drug is DST-2970 tablets (a pharmaceutical formulation according to the present disclosure).

The proposed indication is the treatment of mCRPC in patients with primary resistance to abiraterone.

This study confirms whether DST-2970 tablets are effective in patients with primary resistance to abiraterone. Patients must show a decrease in prostate-specific antigen (PSA) after 3 cycles (1 cycle = 4 weeks) of Zytiga® therapy (1,000 mg abiraterone acetate once daily and 5 mg prednisone twice daily). Is defined as having primary resistance.

For example, the primary objective of this study may include assessing the safety, tolerability, pharmacokinetics, and / or efficacy of DST-2970 tablets in patients with primary resistance to mCRPC and abiraterone therapy. Primary resistance to abiraterone therapy is defined as showing no reduction in prostate-specific antigen (PSA) after 3 cycles of Zytiga® therapy (1,000 mg abiraterone acetate once daily and 5 mg prednisone twice daily). Will be done.

For example, the secondary objective of this study may include ascertaining the pharmacokinetic (PK) profile of abiraterone after administration of DST-2970 to fasted patients, treatments differing in dosage and frequency. ..

The study population is an adult male patient (≧ 18 years) with primary tolerance to mCRPC and abiraterone therapy. Patients are defined as primary resistant if they do not show a decrease in prostate-specific antigen (PSA) after 3 cycles of Zytiga® therapy (1,000 mg abiraterone acetate once daily and 5 mg prednisone twice daily). Will be done.

The trial design and duration can be as follows.

This is a multicenter, open-label patient study evaluating the safety, tolerability, pharmacokinetics, and efficacy of DST-2970 tablets in patients with primary resistance to mCRPC and abiraterone therapy. These are patients who do not show a decrease in prostate-specific antigen (PSA) after 3 cycles of Zytiga® therapy (1,000 mg abiraterone acetate once daily and 5 mg prednisone twice daily).

Randomize up to 100 patients 1: 1 and receive two treatment sequences (study group): Sequence A: DST-2970 tablets once daily (QD); and Sequence B DST-2970 tablets 1 Place in one of three daily (TID) doses. During one cycle, 250 mg initial dose of DST-2970 tablets will be administered according to the dosing regimen for each treatment group. At this point, evaluate each patient's PSA level. If PSA does not decrease by more than 30% per patient, increase the individual dose to 500 mg and perform PSA analysis during the second cycle after dosing according to the treatment group dosing regimen. This repeated dose escalation process is continued until the PSA is reduced by 30% or more for each patient or until the maximum tolerated dose is reached.

The dosage form and route of administration can be as follows.

DST-2970 is supplied as a 50 mg tablet. Patients received a 250 mg initial dose of DST-2970, which was demonstrated to produce abiraterone exposure (AUC) similar to the labeled dose of Zytiga® (1,000 mg fasted) in healthy male subjects. give. The frequency of this initial dose depends on the sequence group assigned to the patient. If PSA does not decrease by more than 30% after the first treatment period, increase the dose of DST-2970 to 500 mg. If PSA does not decrease by more than 30% after the second treatment period, increase the DST-2970 dose to 750 mg. This dose escalation will continue until PSA is reduced by more than 30% or the maximum tolerated dose is reached.

In terms of safety and tolerability, this study confirms whether DST-2970 tablets are safe and well tolerated at all assessed doses and dosing frequencies.

In terms of pharmacokinetics, this study conducted 993 ng ^* hr / in steady state when DST-2970 tablets were administered once daily and / or three times daily and 1,000 mg was administered once daily during fasting. See if increasing doses result in an abiraterone exposure (AUC) that exceeds, or preferably far exceeds, the mean exposure limit of ml Zytiga. For example, AUC in one patient, eg AUC _0-t , or mean levels in multiple patients 1.5x, 2x, 2.5x, 3x, 3.5x, 4x, or more, or Increases of about 1.5 times, about 2 times, about 2.5 times, about 3 times, about 3.5 times, about 4 times, or more may show good results. The study also conducted steady-state 226 ng / ml Zytiga (registered) when DST-2970 tablets were administered once daily and / or three times daily and 1,000 mg once daily at fast. It is also determined whether increasing doses result in peak abiraterone plasma concentrations (C _max ) above or preferably well above the mean (trademark). For example, Cmax in one patient, or average levels in multiple patients are 1.5x, 2x, 2.5x, 3x, 3.5x, 4x, 4.5x, 5x, 5.5x, 6x, 6.5x. Double, 7 times, or more, or about 1.5 times, about 2 times, about 2.5 times, about 3 times, about 3.5 times, about 4 times, about 4.5 times, about 5 times, about 5.5 times, about 6 times , About 6.5 times, about 7 times, or more may show good results. This study also results in an increase in trough avilateron plasma concentration (C _min ), eg, C _min , above 35 ng / mL when DST-2970 tablets are administered once daily and / or three times daily. Also check if it is.

In terms of efficacy, this study responded to improved abiraterone exposure, such as C _max , AUC, and / or C _min , compared to the proven limits of Zytiga® by administration of DST-2970 tablets. See if there is a PSA reduction in at least 20% of patients, eg, a reduction of more than 30%. For example, if this effect is shown in both the once-daily and three-day groups, it may indicate that it is associated with an increase in Cmax and / or AUC. This test checks if the Cmin in the once-daily group is 0 ng / mL or about 0 ng / mL. For example, if this effect is shown only in the triple-daily group, it may indicate an association with maintaining an increase in C _min during the treatment period.

Predictive Example 18: Clinical study in patients with metastatic castile-resistant prostate cancer (mCRPC) and acquired resistance to abiraterone This example is in patients with metastatic castile-resistant prostate cancer (mCRPC) who have acquired resistance to abiraterone. Describe a predictive, multicenter, open-label, dose-escalation study evaluating the safety, tolerability, pharmacokinetics, and anti-PSA activity of DST-2970 tablets.

The investigational drug is DST-2970 tablets (a pharmaceutical formulation according to the present disclosure).

The proposed indication is the treatment of mCRPC in patients with acquired tolerance to abiraterone.

This study will determine if DST-2970 tablets are effective in patients with acquired resistance to abiraterone. Patients were treated with Zytiga® (1000 mg abiraterone acetate once daily and 5 mg prednisone twice daily) for a period of time (eg, at least 12 weeks) compared to pretreatment levels. It may be defined as having acquired resistance if it has previously shown a decrease in PSA, eg, a decrease in PSA of up to 50% or more than 50%, but no longer responds to therapy as indicated by an increase in PSA.

For example, the primary objective of this study may include assessing the safety, tolerability, pharmacokinetics, and / or efficacy of DST-2970 tablets in patients resistant to mCRPC and abiraterone acquisition.

For example, the secondary objective of this study may include ascertaining the pharmacokinetic (PK) profile of abiraterone after administration of DST-2970 to fasted patients, treatments differing in dosage and frequency. ..

The study population is an adult male patient (≧ 18 years old) who is resistant to acquisition of mCRPC and abiraterone therapy.

The trial design and duration can be as follows.

This is a multicenter, open-label patient study evaluating the safety, tolerability, pharmacokinetics, and efficacy of DST-2970 tablets in patients who are resistant to acquisition of mCRPC and abiraterone therapy.

Randomize up to 100 patients 1: 1 and receive two treatment sequences (study group): Sequence A: DST-2970 tablets once daily (QD); and Sequence B DST-2970 tablets 1 Place in one of three daily (TID) doses. The initial 250 mg dose of DST-2970 tablets is administered for one cycle (4 weeks) according to the dosing regimen for each treatment group. At this point, the PSA level of each patient is assessed. If PSA does not decrease by more than 30% per patient, increase the individual dose to 500 mg and perform PSA analysis during the second cycle after dosing according to the treatment group dosing regimen. This repeated dose escalation process is continued until the PSA is reduced by 30% or more for each patient or until the maximum tolerated dose is reached.

The dosage form and route of administration can be as follows.

DST-2970 is supplied as a 50 mg tablet. Patients received a 250 mg initial dose of DST-2970, which was demonstrated to produce abiraterone exposure (AUC) similar to the labeled dose of Zytiga® (1,000 mg fasted) in healthy male subjects. give. The frequency of this initial dose depends on the sequence group assigned to the patient. If PSA does not decrease by more than 30% after the first treatment period, increase the dose of DST-2970 to 500 mg. If PSA does not decrease by more than 30% after the second treatment period, increase the DST-2970 dose to 750 mg. This dose escalation will continue until PSA is reduced by more than 30% or the maximum tolerated dose is reached.

In terms of safety and tolerability, this study confirms whether DST-2970 tablets are safe and well tolerated at all doses evaluated.

In terms of pharmacokinetics, this study showed abiraterone exposure above, or preferably much higher, the average exposure limit of 993 ng ^* hr / ml Zytiga at steady state when 1,000 mg was administered once daily at fast. See if AUC) is provided by the DST-2970 tablets by increasing doses. For example, AUC in one patient, eg AUC _0-t , or mean levels in multiple patients 1.5x, 2x, 2.5x, 3x, 3.5x, 4x, or more, or Increases of about 1.5 times, about 2 times, about 2.5 times, about 3 times, about 3.5 times, about 4 times, or more may show good results. The study also conducted 226 ng / ml Zytiga (registered) at steady state when 1,000 mg was administered once daily at fasting when DST-2970 tablets were administered once daily and / or three times daily. Also see if increasing doses result in peak abiraterone plasma concentrations (Cmax) above or preferably well above the mean of (trademark). For example, C _max in one patient, or mean levels in multiple patients 1.5x, 2x, 2.5x, 3x, 3.5x, 4x, 4.5x, 5x, 5.5x, 6x, 6.5 times, 7 times, or more, or about 1.5 times, about 2 times, about 2.5 times, about 3 times, about 3.5 times, about 4 times, 4.5 times, 5 times, 5.5 times, 6 times, 6.5 times , 7-fold or more may show good results. This study also results in an increase in trough avilateron plasma concentration (C _min ), eg, C _min , above 35 ng / mL when DST-2970 tablets are administered once daily and / or three times daily. Also check if it is.

In terms of efficacy, this study reverses the increasing trend of PSA by administration of DST-2970 tablets or improves abiraterone exposure compared to the proven limits of Zytiga®, ie C _max , AUC, And / or see if there is a PSA reduction in at least 20% of patients, eg, a reduction of more than 30%, corresponding to an improvement in C _min . For example, if this effect is shown in both the once-daily and three-day groups, it may indicate that it is associated with an increase in Cmax and / or AUC. This test checks if the Cmin in the once-daily group is 0 ng / mL or about 0 ng / mL. For example, if this effect is shown only in the triple-daily group, it may indicate an association with maintaining an increase in C _min during the treatment period.

Predictive Example 19: Clinical Trials in Patients with Triple Negative Breast Cancer (TNBC) This Example is a predictive evaluation of the safety, tolerability, and antitumor activity of DST-2970 tablets in patients with triple negative breast cancer (TNBC). A multicenter, open-label, dose-escalation study will be described.

The investigational drug is DST-2970 tablets (a pharmaceutical formulation according to the present disclosure).

The proposed indication is the treatment of TNBC.

This study will determine if DST-2970 tablets are effective in patients with TNBC. TNBC is a cancer that has been negatively tested for estrogen receptor, progesterone receptor, and excess HER2 protein.

For example, the primary objective of this study may include assessing the safety, tolerability, and efficacy of DST-2970 tablets in TNBC patients. Primary outcome items include pathologic complete response (pCR). Secondary outcome items include overall survival (OS).

The criteria for inclusion in this study may be:

Histologically or cytologically confirmed triple-negative invasive breast cancer; clinical stage IIA-IIIB. Patients have palpable lesions with calipers and / or measurable disease as defined by positive mammograms or ultrasound. Bilateral mammograms and clip placements are required for study enrollment. Baseline measurements of indicator lesions are recorded on the Patient Registration Form. To be effective at baseline, measurements must be taken within 14 days if palpable. If palpation is not possible, a mammogram or MRI must be done within 14 days. If palpation is possible, perform mammogram or MRI within 2 months prior to study enrollment. If clinically indicated, x-rays and scans should be done within 28 days of study enrollment. Within 2 weeks of enrollment, the patient must have sufficient organ function as indicated by: Absolute neutrophil count> 1500 / mm3, Hgb> 9.0 g / dl, and Bilirubin count> 100,000 / mm3, Total bilirubin <upper normal, creatinine <1.5 mg / dL, or calculated anterior cruciate ligament (CrCL) formula using the Cockcroft Gault equation> 50 mL / min. Serum glutamate oxaloacetate transaminase (SGOT) (AST), or serum glutamic oxaloacetic transaminase (SGPT) (ALT), and alkaline phosphatase should be acceptable. Must be. The patient must be at least 18 years old. Women who can give birth must have a negative serum pregnancy test performed within 7 days prior to the start of treatment. Women and men who can give birth must agree to use appropriate contraceptive methods (barrier birth control) before enrollment and during study participation.

The trial design and duration can be as follows.

This is a multicenter, open-label, dose-escalation study evaluating the safety, tolerability, and efficacy of DST-2970 tablets in TNBC patients. These are patients with breast cancer who tested negative for the estrogen receptor, progesterone receptor, and excess HER2 protein.

Randomize up to 100 patients 1: 1 and receive two treatment sequences (study group): Sequence A: DST-2970 tablets once daily (QD); and Sequence B DST-2970 tablets 1 Place in one of three daily (TID) doses. The initial 250 mg dose of DST-2970 tablets is administered for one cycle (4 weeks) according to the dosing regimen for each treatment group. A biopsy is performed at this point to assess the pathologic response (PR). If no tumor response is observed per patient, increase the individual dose to 500 mg and perform biopsy and PR evaluation after administration according to the treatment group dosing regimen during the second cycle. This repeated dose escalation process is continued until a response appears for each patient or until the maximum tolerated dose is reached.

The dosage form and route of administration can be as follows.

DST-2970 is supplied as a 50 mg tablet. Patients are given an initial dose of 250 mg DST-2970. The frequency of this initial dose depends on the sequence group assigned to the patient. If there is no tumor response after the first treatment period, increase the dose of DST-2970 to 500 mg. If there is no response after the second treatment period, increase the DST-2970 dose to 750 mg. This dose escalation continues until a tumor response appears or the maximum tolerated dose is reached.

In terms of safety and tolerability, this study confirms whether DST-2970 tablets are safe and well tolerated at all doses evaluated.

In terms of efficacy, this study confirms whether administration of DST-2970 tablets improves pCR and OS statistically significantly. For example, efficacy may have been observed in relation to high systemic exposure to abiraterone and, as a result, highly effective androgen receptor (AR) pathway targeting. For example, if this effect is seen in both the once-daily and three-day groups, it may indicate that it is associated with an increase in Cmax and / or AUC. This test checks if the Cmin in the once-daily group is 0 ng / mL or about 0 ng / mL. For example, if this effect is shown only in the triple-daily group, it may indicate an association with maintaining an increase in C _min during the treatment period.

Predictive Example 20: Clinical study in patients with non-metastatic castration-resistant prostate cancer (nmCRPC) This example is a predictive DST-2970 tablet vs. parttamide in a man with non-metastatic castration-resistant prostate cancer (nmCRPC). Describe multicenter, comparative, randomized, double-blind, parallel-group, active controls, and clinical superiority trials.

The investigational drug is DST-2970 tablets (a pharmaceutical formulation according to the present disclosure).

The proposed indication is the treatment of nmCRPC.

This study will determine whether DST-2970 tablets show superior efficacy compared to appartamide in patients with non-metastatic castration-resistant prostate cancer, as indicated by the delayed onset of metastasis. The superior efficacy may be related to the ability to target the androgen receptor (AR) pathway more effectively by increasing systemic abiraterone levels.

For example, the primary objective of this study may include assessing the safety and efficacy of DST-2970 tablets vs. partamide in adult males with nmCRPC. Key items of efficacy include metastatic survival (MFS) by the Blinded Independent Central Review (BICR). MFS refers to the time from randomization to the first evidence of distant metastasis to bone or soft tissue confirmed by BICR or death from any cause, whichever occurs first. X-ray scans (bone scans of the chest, abdomen, and pelvis and computer tomography [CT] or magnetic resonance imaging [MRI]) are performed to detect metastases throughout the study.

For example, the secondary objectives of this study may include:

Time to metastasis (TTM). For example, it is defined as the time from randomization to the scan time, as confirmed by BICR, showing the first evidence of distant metastasis to bone or soft tissue detected by radiography. X-ray scans (chest, abdomen, and pelvic bone scans and CT or MRI) are performed to detect metastases throughout the study.

Progression-free survival (PFS). For example, from randomization, whichever first occurs, the first is progressive disease (PD) (distant metastasis / local metastasis / localized metastasis) confirmed by radiography confirmed by BICR or death from any cause. It is defined as the time until it is recorded in. X-ray scans (chest, abdomen, pelvic bone scans and CT / MRI) are performed to detect metastases throughout the study. PD may be based on Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. For subjects with measurable lesions, referring to the smallest sum at the time of the test, an increase in the sum of the diameters of the target lesions by at least 20% and / or an absolute increase by at least 5 mm is considered PD. In some cases. Also, the appearance of one or more new lesions may be considered PD. Also, in subjects with diseases that cannot be measured by CT / MRI scans, a clear progression / appearance of one or more new lesions may also be considered PD. For new bone lesions detected by bone scintigraphy, second imaging (CT / MRI) may be required to confirm PD.

Time to symptomatic progression. For example, from randomization, one of the following (which may occur first): a) Onset of skeletal-related events (pathological fracture, spinal compression, or the need for surgical intervention or radiation therapy on the bone): B) Pain progression or exacerbation of disease-related symptoms requiring the initiation of new systemic anticancer therapy; or c) Clinical significance of localized tumor progression requiring surgical intervention or radiation therapy It is defined as the time it takes for the onset of a condition to be recorded.

Overall survival. For example, it is defined as the time from randomization to the date of death from any cause.

Time to start cytotoxic chemotherapy. For example, it is defined as the time from randomization to the start date of cytotoxic chemotherapy for prostate cancer.

The criteria for inclusion in this study may be:

Histologically or cytologically confirmed prostate cancer with neither neuroendocrine differentiation nor small cell features at high risk of developing metastases. For example, it is defined as a prostate-specific antigen doubling time (PSADT) that is less than or equal to 10 months (<=). PSADT can be calculated using at least three prostate-specific antigen (PSA) levels obtained during continuous ADT (androgen deprivation therapy). The patient has castration-resistant prostate cancer that has been proven during continuous ADT. This is defined as, for example, three PSAs rising at least one week apart and the final PSA greater than 2 nanograms / milliliter (ng / mL) (>). Patients maintain castrate levels of testosterone within 4 weeks prior to randomization and throughout the study. Patients currently receiving bone loss prophylaxis with bone-sparing medications are taking stable doses for at least 4 weeks prior to randomization. Patients receiving first-generation antiandrogens (eg, bicalutamide, flutamide, nilutamide) have at least a 4-week washout period prior to randomization and continued disease (PSA) progression (PSA increase) after the washout period. ) Must be shown. At least 4 weeks have passed since the use of 5-α reductase inhibitors, estrogens, and any other anticancer therapies prior to randomization. At least 4 weeks have passed since major surgery or radiation therapy prior to randomization. Patients show resolution of all acute toxic effects of pretreatment or surgical treatment to grade <= 1 or baseline prior to randomization. The patient has sufficient organ function according to the criteria defined by the protocol. Growth factor administration and blood transfusions may not be permitted within 4 weeks of the blood test required to confirm eligibility.

The trial design and duration can be as follows.

This is a multicenter, comparative, randomized, double-blind, parallel group, active control, clinical superiority study of DST-2970 tablets vs. partamide in men with nmCRPC.

Patients were randomized 1: 1 and two treatment sequences (study group): Sequence A: 240 mg once-daily (QD) administration of Apartamide tablets; and Sequence B: 400 mg of DST-2970 tablets daily. Place in one of a single dose. Patients are regularly evaluated for signs of metastasis according to the items above. The statistically significant improvement in metastasis-free survival indicates the superiority of DST-2970 over appartamide.

The dosage form and route of administration can be as follows.

Apartamide is supplied as a 60 mg tablet. DST-2970 is supplied as a 50 mg tablet. Tablets are orally administered according to the sequence dosing regimen.

In terms of safety and tolerability, this study confirms whether DST-2970 tablets are safe and well tolerated at all doses evaluated.

In terms of efficacy, this study confirms whether administration of DST-2970 tablets statistically significantly improves primary and secondary items to appartamide. For example, efficacy may be observed in connection with large systemic exposure to abiraterone and, as a result, highly effective androgen receptor (AR) pathway targeting.

Prophecy Example 21: The present disclosure of an active or modified form of abiraterone, eg, a pharmaceutically acceptable salt, ester, derivative, analog, prodrug, hydrate, or solvate compound thereof. Pharmaceutical formulations of abiraterone or abiraterone acetate. The exemplary formulations described in the examples herein are intended to show the same or similar results in terms of pharmacokinetics and therapeutic efficacy. Thus, active abiraterone and modified abiraterone, eg, pharmaceutically acceptable salts, esters, derivatives, analogs, prodrugs, hydrates, or solvates thereof are the same in terms of pharmacokinetics and therapeutic effects. Or it is intended to show similar results.

Example 22: Materials and Methods of Examples 23-28 The following materials were used to produce the results described in Examples 23-28.

Ingredients Avilaterone active ingredient (API) was purchased from Attix Pharma (Ontario, Cannada). Hydroxypropyl β-cyclodextrin, Kleptose® HPB, was purchased from Roquette America (USA). Crystalline cellulose, ie Avicel PH-102, was purchased from FMC Corporation (Pennsylvania, USA). Mannitol, or Pearlitol 200SD, was purchased from Roquette America (USA). Cross-linked sodium carboxymethyl cellulose, ie Vivasol®, was purchased from JRS Pharma (New York, USA). Hypromellose acetate HMP grade, ie AQOAT®, was purchased from Shin-Etsu (New Jersey, USA). Colloidal silicon dioxide, ie Aerosil® 200 P, was purchased from Evonik Industries (New Jersey, USA). Magnesium stearate was purchased from Peter Greven (Muenstereifel, Germany). The fasting simulated intestinal juice (FaSSIF) elution medium was prepared from FaSSIF / FeSSIF / FaSSGF powder purchased from Biorelevant.com (Surrey, UK). Abiraterone acetate tablets, ie Zytiga® (250 mg abiraterone acetate), were purchased from a pharmacy and manufactured for Janssen Biotech (Pennsylvania, USA). The solvent used for the HPLC analysis was HPLC grade. All other chemicals and reagents used for elution and HPLC analysis were ACS grade.

The results described in Examples 23-28 were obtained using the following methods.

KinetiSol® Treated Abiraterone with different drug loadings KinettiSol® Solid Dispersion (KSD) was prepared using KinettiSol® Technology (DisperSol Technologies LLC, Texas). Initially, all KSDs were prepared using a research-scale compounder (“Formulator”) designed and manufactured by DisperSol Technologies LLC (Texas, USA). Amorphous KSDs were then prepared using a manufacturing scale compound designed and manufactured by DisperSol Technologies LLC (Texas, USA) (“Manufacturing compounder”). Prior to compounding, the drug abiraterone and the oligomer HPBCD (Table 3.1) were accurately weighed and mixed well to prepare a physical mixture (PM). The physical mixture was packed into a KinettiSol® compounder chamber. Inside the chamber, a shaft with protruding blades was rotated at a variable speed of gradual acceleration from 500 rpm to 7000 rpm to apply friction and shear forces to the sample material without applying external heat. The temperature of the mass was monitored using an infrared probe. When the temperature of the molten mass reached a value of 150-180 ° C, the mass was quickly ejected, collected and pressed between two stainless steel plates for quick quenching of the sample.

Crush
Quenched mass obtained after KinetiSol® treatment is ground in small portions using a lab scale rotor mill, i.e., IKA Works GmbH & Co. KG, Staufen, Germany. bottom. For grinding, pieces of the quenched mass were filled into a 20 mL grinding chamber and run at a grinding rate of 10,000-20000 rpm for 60 seconds. The ground material was then passed through a # 60 mesh screen (≤250 μm). Material retained on the screen, ie> 250 μm, was circulated through a mill with the same parameters and this grinding and sieving process was repeated until all material passed through the screen. The resulting <250 μm material was called KSD.

Melt-quenching Abiraterone Melt-quenching was used to prepare pure amorphous Avilateron reference samples for nuclear magnetic resonance spectroscopy and Raman spectroscopy. A small amount of abiraterone (<0.5 g) was added to an open scintillation vial and treated with a blow torch for a few seconds until the total amount of abiraterone had melted. The scintillation vial containing the molten mass was immediately submerged in liquid nitrogen. When the intensity of nitrogen boiling diminished, the vials were transferred to a vacuum desiccator and depressurized for approximately 2 hours. After 2 hours, the decompression was released and the vial was removed from the desiccator. The quenched abiraterone mass was scraped from the vial, lightly ground with a pestle and screened with a # 60 mesh screen (≤250 μm). The melt-quenched abiraterone was placed in the freezer until further use.

Modulated differential scanning calorimetry Thermal analysis was performed by modulated differential scanning calorimetry (mDSC) using a differential scanning calorimetry model Q20 (TA Instruments, Delaware, USA) equipped with a refrigeration-based cooling system and an autosampler. API and KSD samples were prepared by weighing 5-10 mg material and loaded into a Tzero pan. The pan was sealed with a Tzero lid using a Tzero press. After equilibrating the sample at 30 ° C. for 5 minutes, the temperature was raised to 250 ° C. at 5 ° C./min with an adjustment of ± 1 ° C. every 60 seconds. Nitrogen was used as a sample purge gas at a flow rate of 50 mL / min. Data were collected using TA Instrument Explorer software (TA Instruments, Delaware, USA) and processed using Universal Analysis software (TA Instruments, Delaware, USA).

HPLC Analysis A High Performance Liquid Chromatography (HPLC) method has been developed for abiraterone KSD chemical analysis. A Dionex Ultimate 3000 HPLC system (Thermo Fisher Scientific, Massachusetts, USA) was used for reverse phase HPLC analysis. The HPLC column was Kinetex® XB C18, 150mmx4.6mm, 2.6μm (Phenomenex, California, USA). Mobile phase A was 20 mM ammonium formate buffer (pH 3) and mobile phase B was degassed acetonitrile. First, we designed a gradient profile with a water-rich phase followed by a gradual increase in the organic phase. The flow rate was 0.9 mL / min and the runtime was 42 minutes. The column was kept at 35 ° C. and data was collected at a single wavelength of 254 nm. Samples were prepared with a nominal concentration of 0.5 mg / mL level using 7: 2: 1 methanol: isopropyl alcohol: tetrahydrofuran as a standard / sample diluent. Prior to analysis, all samples were filtered through a 0.45 μm PVDF syringe filter (GE Healthcare Life-Sciences, Pennsylvania, USA). Sample chromatography was analyzed using Chromeleon ™ software, version 7.0 (Thermo Fisher Scientific, Massachusetts, USA).

Solid-State Nuclear Magnetic Resonance Spectroscopy One-Dimensional (1D) ¹³ C Solid-State Nuclear Magnetic Resonance Spectroscopy (ssNMR) was performed at the NMR Lab, University of Texas at Austin (Texas, USA). ¹³ C ss NMR spectra were collected using a Bruker AVANCE ™ III HD 400 MHz instrument (Bruker Corporation, Massachusetts, USA). A cross polarization experiment was performed with a 4 mm MAS probe and the ¹³ C frequency used was 100.62 MHz. The contact time was set to 2 ms, the spin rate was set to 10 KHz, and the relaxation delay was 2 to 30 seconds. The temperature was set to 300.0K. A chemical shift standard product, adamantane, 38.48 ppm was used. Data were collected using Bruker NMR software (Bruker Corporation, Massachusetts, USA). Data was processed using MNOVA software, version 14 (Santiago de Compostela, Spain).

In the Biopharmaceutical NMR Laboratory (BNL) of Preclinical Development of Merck Research Laboratories (Merck & Co., Inc. West Point, PA), a two-dimensional (2D) ¹³ C-1H heteronuclear correlation (HETCOR) spectrum was obtained at ¹ of 400.13 MHz. Obtained using a Bruker AVANCE III HD 400 triple-resonance spectrometer operating at H frequency. An experimental temperature of 298 K and a MAS frequency of 12 kHz were used. All data was processed by Bruker TopSpin software. ¹³ C- ¹ H HETCOR experiments were performed with a CP contact time of 2 ms and a recycle delay of 2 seconds.

Raman spectroscopy Raman spectroscopy was performed using HyperFlux ™ PRO Plus (HFPP) Raman spectroscopy systems (Tornado Spectral Systems, Ontario, Canada). API, PM, KSD, and melt-quench abiraterone samples were loaded onto an aluminum stage. The sample was subjected to a laser beam with a wavelength of 785 nm and an output of 200 mW. 50 exposures were collected per spectrum and 3 spectra were collected per sample. An exposure time of 100 ms was used. It enabled the removal of cosmic rays and the correction of dark spectra. Spectral data were collected using SpectralSoft software (Tornado Spectral Systems, Ontario, Canada). Preprocessing and multivariate analysis of spectral data was performed using Unscrambler X software (Camo Analytics, Oslo, Norway).

Phase Solubility Analysis Phase solubility analysis was performed in two separate mediums, namely 0.01N HCl (pH 2.0) and FaSSIF (prepared with 50 mMol phosphate buffer pH 6.8). A 0 mg / mL to 600 mg / mL HPBCD solution was prepared by dissolving in each medium in a scintillation vial. Excess abiraterone was added to each vial and the vials were sonicated for 30 minutes and placed on a laboratory table. Samples were removed from each vial at 48 hours and 7 days. Samples were centrifuged using an ultracentrifuge (Eppendrof, Hamburg, Germany). The supernatant was further diluted with an HPLC diluent and analyzed by the HPLC method described above to determine the abiraterone concentration.

Stability analysis Stability analysis was performed at high temperature. KSD samples were filled into scintillation vials and heated on a 90 ° C. hot plate for 6 hours. The sample was then analyzed by XRPD as described above. During the XRPD analysis, the sample was reheated on a hot plate at 150 ° C. for 6 hours and the sample was reanalyzed by XRPD.

In vitro Elution Test An in vitro non-sync gastric mobile elution method was developed to analyze the elution of abiraterone API and KSD. For elution analysis, a sample equivalent to 44.6 mg Avilateron API was placed in an Erlenmeyer flask (eluting vessel) containing 50 ml 0.01N HCl (pH 2.0) and set to a rotation speed of 37 ° C and 180 rpm. Placed in an incubator shaker Excella E24 (New Brunswick Scientific, New Jersey, USA). After 30 minutes, 50 ml of FaSSIF (prepared by dissolving in 50 mMol phosphate buffer pH 6.8) was added to the elution vessel. At a predetermined point in time, the sample was withdrawn from the elution vessel and centrifuged using an ultracentrifuge (Eppendrof, Hamburg, Germany). The supernatant was further diluted with an HPLC diluent and analyzed by the HPLC method described above. The area under the drug elution curve (AUDC) was calculated by the linear trapezoidal method.

Tableting
Exactly KSD and tableting excipients Avicel PH-102, Pearlitol 200SD, Vivasol®, Kleptose®, AQOAT®, Aerosil® 200 P, and magnesium stearate. Weighed and distributed. Aerosil® 200P was sieved with # 40 (420 μm) until all material passed through the sieve. KSD and all tableting excipients except magnesium stearate were filled into vials and mixed using a vortex mixer (Thermo Scientific, Massachusetts, USA). Magnesium stearate was then added to the vials and blended using a spatula. The resulting tableted blend was then dispensed with an aliquot equivalent to 50 mg abiraterone. Each aliquot was filled into a tablet die and compressed to a target hardness of 8-12 kP using a single station hand tablet press (BVA Hydraulics, Missouri, USA). ..

In vivo pharmacokinetic studies in beagle dogs In vivo pharmacokinetic studies in fasted non-naive male beagle dogs were performed at Pharamaron (Ningbo, China). Animal studies were performed according to the approved Pharmalon IACUC protocol # PK-D-06012018. 50.0 mg equivalent abiraterone tablets were analyzed together with 250 mg equivalent abiraterone acetate tablets-ZYTIGA®. Each test group of each formulation was not from 3 dogs. Dogs were fasted overnight before dosing and returned to food 4 hours after dosing. Each dog was administered one tablet of each formulation (according to the test group) and was flushed with 40 mL of sterile water after dosing. 0.25 hours, 0.5 hours, 1 hour, 1.5 hours, 2 hours, 3 hours, 4 hours, 6 hours, 8 hours, 10 hours, 12 hours, 16 hours after dosing. A 1 mL blood sample was withdrawn from each dog by venous puncture of peripheral blood vessels at 18 hours, 24 hours, 36 hours, and 48 hours, and contained heparin sodium anticoagulant. I put it in a tube. Blood samples were centrifuged to isolate plasma. Plasma samples were analyzed using liquid chromatography-tandem mass spectrometry (LC-MS / MS) to determine the avilateron content.

を用いて計算した。 Pharmacokinetic Analysis Pharmacokinetic parameters were estimated using Phoenix ™ WinNonlin software version 6.1 (Certara, NJ, USA) using a non-compartmental approach consistent with the oral route of administration. The area under the plasma concentration-time curve (AUC) was calculated by the linear trapezoidal method. Relative bioavailability, that is, the F value, is expressed by the following formula:

Was calculated using.

Example 23: Preparation of Kinetti Sol® Solid Dispersion (KSD) Table 19 lists the KSD compositions and processing parameters. Lots 1-5 PM could all be processed by KinettiSol® technology. First, all lots were processed with a research scale compounder. Then, for further testing, lots 1-3 KSD were treated with a manufacturing scale compounder to obtain a larger amount of material. The total processing time for lots 1 to 4 KSD was less than 20 seconds, while the total processing time for lot 5 KSD was 41.5 seconds. A significant amount of material adhesion was observed for lots 4 and 5 KSD. All lots were easily ground and sieved with # 60 to obtain KSD powder with a particle size of <250 μm.

(Table 19) KSD composition and processing parameters

Traditionally, drug-CD pharmaceutical compositions have been solvent-based (eg, organic solvents, carbon dioxide) based techniques such as spray drying, lyophilization, solvent evaporation, solvent kneading, and super. It has been prepared by a critical fluid process (Modekar and Patil 2016; Jug, Becirevic-Lacan, and Bengez 2009; Gala 2015; Jug and Mura 2018; Semcheddine et al. 2015; Li et al. 2018). Limited scalability, high energy consumption, use of toxic organic solvents, difficulty in solvent removal, potential drug degradation, etc. related to these techniques There are some drawbacks (Jug and Mura 2018). Certain solvent-free techniques such as microwave irradiation, sealed heating, and hot melt extrusion have also been reported for the preparation of drug-CD pharmaceutical compositions (Thiry et al. 2017; Wen et al. 2004; Mura et al. 1999). The main difficulty with these techniques is the decomposition of the drug by microwave irradiation or heating (Jug and Mura 2018). Grinding is another solvent-free method that has been used to prepare drug-CD pharmaceutical compositions (Ramos et al. 2013; Borba et al. 2015). Typical grinding times for drugs-CDs range from approximately minutes to hours (Jug and Mura 2018). When the drug is subjected to high physical pressure over a long period of time, which is peculiar to the grinding process, the drug can be decomposed in a large amount (Savjani, Gajjar, and Savjani 2012). KinetiSol® is a thermodynamic solvent-free technique that does not require the application of external heat, with typical processing times of approximately seconds, typically <30 seconds (Ellenberger, Miller, and). Williams 2018). Therefore, KinettiSol® is a promising technique for treating drug-CD pharmaceutical compositions.

Using KinetiSol® technology, an abiraterone-HPBCD KSD with a drug loading of 10% to 50% was first developed on a research scale compounder (ie, formulater). The formulater can process up to 15g of material per batch, making it suitable for small-scale formulation screening and feasibility testing (Ellenberger, Miller, and Williams 2018). Manufacturing-scale compounds, on the other hand, are also known as manufacturing compounds and can process up to 350 g of material per batch, making them suitable for making preclinical and early stage clinical supplies (Ellenberger, Miller). , and Williams 2018). Lots 1-3 KSD were to be tableted for animal testing, so these lots were recreated with a manufacturing compound to increase the amount of KSD. The processing parameters for lots 1-3 PM were easily transferred from the formulator to the manufacturing compounder using the scaling factor. This proves that KinettiSol® is an extensible technology. A 10% -40% drug loading amount (ie, lots 1-4 KSD) requires a total processing time (<20 seconds) to reach the target temperature, while a 50% drug loading lot 5 KSD total processing time (<20 seconds). It was found to be shorter than 41.5 seconds) (Table 19). This may be because a large amount of shear stress is required over a long period of time to thermodynamically treat the abiraterone, which is abundantly present. The treatment temperatures for all five lots were comparable, ranging from 150 to 180 ° C (Table 19). For lots 3-5 KSD, slow rotation speeds, ie 500 rpm, 1000 rpm, and 1000 rpm, respectively, were initially adopted to ensure uniform drug mixing as they contain large drug loadings. After that, faster rotation speeds, namely 2700 rpm, 6000 rpm, and 6000 rpm, respectively, were adopted (Table 19). Lot 4 and Lot 5 KSDs contained large amounts of molten abiraterone, which led to material sticking. This problem can be easily solved by adding a lubricant such as sodium stearyl fumarate.

Overall, KSD with a drug loading of 10% to 50% was treatable by KinettiSol® technology and was easily quenched, ground and sifted to give KSD powder.

Example 24: Physicochemical analysis of KSD Figure 28 illustrates an X-ray diffraction pattern of pure abiraterone API, melt-quenched abiraterone API, HPBCD, lot 1 PM, and lots 1-5 KSD. The X-ray diffraction pattern of the pure abiraterone API showed sharp diffraction peaks. This figure showed characteristic peaks at 8.43 °, 16.54 °, and 19.31 °. The melt-quenched abiraterone API X-ray diffraction pattern did not show sharp diffraction peaks, but showed a halo pattern. The HPBCD X-ray diffraction pattern also showed a halo pattern. The X-ray diffraction pattern of Lot 1 PM showed a sharp diffraction peak. It showed sharp peaks at 8.70 °, 16.72 °, and 19.55 °, corresponding to the characteristic peaks of the pure abiraterone API. In addition, Lot 1 PM peaked at 12.08 °, 15.51 °, 17.29 °, 21.48 °, and 23.98 °, which differed slightly in terms of peaks and positions observed on the pure abiraterone API diffractogram. X-ray diffraction charts of lots 1-3 KSD showed a complete halo pattern and no diffraction peaks. X-ray diffractograms of lots 4 and 5 KSD showed sharp diffraction peaks at 8.52 °, 16.54 °, and 19.60 °, corresponding to the characteristic peaks of the pure abiraterone API. In addition, lots 4 and 5 KSD showed certain, smaller diffraction peaks, which were also observed in the pure abiraterone API diffraction chart.

The mDSC thermograms for Lot 1 PM and Lot 1-5 KSD are illustrated in Figure 29. Lot 1 PM showed sharp melt endothermic at 227.25 ° C. Lot 2 and Lot 3 KSD showed no significant thermal events under the evaluated mDSC operating conditions. Lot 3 KSD showed a small thermal event at 216.20 ° C and melt endothermic at 224.72 ° C. Lot 4 KSD showed a wide range of melt endothermic at 219.99 ° C. Similarly, Lot 5 KSD showed melt endothermic at 223.62 ° C.

HPLC analysis revealed that lots 1-3 KSD had 0.28%, 0.37%, and 0.38% total impurities, respectively. None of these lots were free of individual unknown impurities of ≧ 0.2%.

The X-ray diffraction pattern of the pure abiraterone API (Fig. 28) showed sharp diffraction peaks, thereby showing crystalline properties. The melt-quenched abiraterone API showed a halo XRPD pattern (Fig. 28). Therefore, it is suggested that abiraterone was converted to a pure amorphous form. It is well known that pure amorphous APIs are extremely unstable and have a strong tendency to recrystallize (Knapik-Kowalczuk et al. 2019). Therefore, to prevent recrystallization, the Melt Quenchia virateron API was stored in a freezer below 0 ° F. The HPBCD X-ray diffraction pattern (Fig. 28) showed a halo pattern similar to that reported by Gala and Ren et al. It shows that HPBCD is amorphous in its state (Gala 2015; Ren et al. 2009). Natural CD is crystalline in state due to the presence of intermolecular hydrogen bonds (Gala 2015; Loftsson et al. 2005). However, when the intermolecular hydrogen bond is broken by alkyl substitution, modified CDs such as HPBCD become amorphous properties (Sharma and Baldi 2016; Loftsson et al. 2005). Lot 1 PM showed a sharp diffraction peak (Fig. 28), thus showing its crystalline properties. The slightly different XRPD peak positions in lot 1 PM compared to the pure abiraterone API are due to the contribution of the HPBCD amorphous halo pattern in lot 1 PM. Lot 1-3 KSDs showed a halo XRPD pattern (Fig. 28), thus indicating that the abiraterone API was converted to amorphous in these KSDs. However, the sharp diffraction peaks observed in the X-ray diffraction patterns of Lot 4 and Lot 5 KSDs showed that the abiraterone API in these KSDs was predominantly crystalline. Also, since the diffraction peaks observed for Lot 4 and Lot 5 KSDs mostly coincided with the peaks of the pure abiraterone API, KinetSol® technology developed the polymorphic shape of the abiraterone API within these KSDs. It can be inferred that it did not change.

The melting peak observed in the mDSC thermogram of Lot 1 PM (Fig. 28) coincided with the melting point of abiraterone at around 228 ° C (Solymosi et al. 2018). No melt endothermic corresponding to the abiraterone API was observed in the mDSC thermograms of Lot 2 and Lot 3 KSD, further confirming that the abiraterone API was converted to amorphous form in these lots. Interestingly, two small thermal events observed in the lot 3 KSD mDSC thermogram (Figure 29) show that a certain amount of abiraterone in the lot 3 KSD is still crystalline. However, this contradicts the XRPD pattern of Lot 3 KSD. Therefore, we analyzed the irreversible heat flow v / s temperature profile (data not shown) of the Lot 3 KSD mDSC thermogram and before the melt endothermic observed in the reversible heat flow v / s temperature profile. Two widespread endothermic recrystallizations were observed in. From this, it can be seen that the melting event was mainly caused by the mDSC operating parameters. Extensive melt endothermic observed in the mDSC thermograms of Lot 4 and Lot 5 KSD showed that the crystalline abiraterone API had melted, supporting observations in the XRPD diffractogram (Figure 28). .. It should be noted that the melt endothermic observed for Lot 4 and Lot 5 KSD occurred at temperatures below the melting point of the abiraterone. This may be due to the interaction between the well-mixed abiraterone-HPBCD mixture and the abiraterone-HPBCD due to thermodynamic treatment with KinettiSol® technology (Gala, Pham, and). Chauhan 2013).

Since the total percent purity of abiraterone in all KSDs was> 99.50%, it can be concluded that abiraterone did not degrade during the Kinetti Sol® process.

Thus, overall, KinettiSol® technology was able to make KSDs with a drug loading of 10% to 30% into a physically amorphous and chemically stable form. ..

Example 25: Solid-state interaction of abiraterone with HPBCD inside the KSD Figure 30 illustrates the ¹³ C ss NMR spectra of pure abiraterone API, HPBCD, lots 1 PM, and lots 1-5 KSD. The 1D ¹³ C ss NMR spectrum of the pure abiraterone API showed 21 sharp signals. It showed 11 signals of 20-60ppm, one signal of about 72ppm, and 9 signals of 120-160ppm. HPBCD showed 6 broad signals at about 19ppm, 61ppm, 67ppm, 73ppm, 82ppm, and 102ppm. Lot 1 PM showed a mixture of sharp and broad signals corresponding to both pure abiraterone API and HPBCD. Lots 1-3 KSD showed a major signal corresponding to HPBCD. They showed some broad signal of 20-60 ppm corresponding to the pure abiraterone API, but in the lot 1-3 KSD ¹³ C ss NMR spectrum, there was no signal of 120-160 ppm corresponding to the pure abiraterone API. It was either or considerably wider. Lot 4 and Lot 5 KSD showed a mixture of sharp and broad signals corresponding to both pure abiraterone API and HPBCD.

The raw Raman spectra of the melt-quenched abiraterone API and KSD showed fluorescence interference. Therefore, the raw spectrum is transformed into a second derivative using a second-degree polynomial and a Savitzky-Golay 31-point smoothing filter. Processing was performed. The second derivative spectrum was then scatter-corrected by applying a standard normal variate transformation. Table 20 lists the Raman peak positions for the pure abiraterone API, melt-quenched abiraterone API, lot 1 PM, and lots 1-5 KSD. Table 21 lists the raman peak shifts for the melt-quenched abiraterone API, lot 1 PM, and lots 1-5 KSD. In detail, the Raman peak positions corresponding to the pyridine ring vibration, steroid partial vibration, and C = C vibration in the B and D rings of abiraterone are listed. For melt-quenched APIs, we listed the peak shifts for the pure abiraterone API. For Lot 1 PM and Lot 4 and Lot 5 KSD, all of these contain primarily crystalline abiraterone, so peak shifts to the pure abiraterone API were calculated. For lots 1-3 KSD, all of these contained primarily amorphous abiraterone, so peak shifts to the melt-quenched abiraterone API were calculated.

(Table 20) Raman peak positions for pure abiraterone API, melt-quenched abiraterone API, lot 1 PM, and lots 1-5 KSD

(Table 21) Raman peak shifts for melt-quenched abiraterone API, lot 1 PM, and lots 1-5 KSD

The 1D ¹³ C ss NMR spectra of pure abiraterone API, lot 1 PM, lot 4 and 5 KSD (Fig. 30) showed a major sharp signal, which showed crystalline properties. In contrast, the ¹³ C ss NMR spectra of HP BCD and lots 1-3 KSD (Fig. 30) show a wide range of major signals, thereby exhibiting amorphous properties. This further confirms our inferences from X-ray diffraction and modulation differential scanning calorimetry. To understand solid-state interactions within the KSD, we first assigned a ¹³ C ss NMR signal to carbon atoms at abiraterone and HPBCD. In the ¹³ C ss NMR spectrum of the pure abiraterone API, signals from 20 ppm to 60 ppm can be assigned to the sp ³ hybrid carbon of abiraterone. The sp ³ hybrid carbons of avilateron are C1, C2, C4, C6, C8, C9, C10, C11, C12, C13, C14, C15, C23, and C24. A signal of about 72 ppm can be assigned to C3 and a signal of 120 ppm to 160 ppm can be assigned to the sp ² hybrid carbon of abiraterone. The sp ² hybrid carbons of abiraterone are C5, C7, C16, C17, C18, C19, C20, C21, and C22. In the ¹³ C ss NMR spectrum of HPBCD, the signal assignment is 19 ppm (hydroxypropyl group) of glupyranose units in HPBCD; 61 ppm (C6); 67 ppm (hydroxypropyl group); 73 ppm (C2, C3, C5). 82ppm (C4) and 102ppm (C1). Similar HP BCD ¹³ C ss NMR spectra have been reported in the literature (Pessine, Calderini, and Alexandrino 2012). Since the ¹³ C ss NMR spectrum of Lot 1 PM showed additional signals from both the pure abiraterone API and HPBCD, it can be inferred that there is no interaction between abiraterone and HPBCD in PM. Since there is no abiraterone sp ² hybrid carbon signal between 120 ppm and 160 ppm in the Lot 1 KSD ¹³ C ss NMR spectrum, the abiraterone B, D, and pyridine rings interact with HPBCD and cover the interior of the HPBCD cavity. It turns out that it is likely to be / included. For Lot 2 and Lot 3 KSD, these signals are broadened, thus indicating some interaction between the B, D, and pyridine rings of the abiraterone and the HPBCD, but the Lot 1 KSD. Unlike, not all amorphous abiraterones in these lots interact with HPBCD. The absence of the abiraterone C3 signal in the ¹³ C ss NMR spectra of lots 1-3 KSD and the widening of the abiraterone sp ³ hybrid carbon signal at 20 ppm to 60 ppm resulted in abiraterone A-rings, C-rings and HPBCD in these lots. It is suggested that they interact. Since the ¹³ C ss NMR spectra of Lot 4 and Lot 5 KSD show peaks and minimal widening corresponding to both abiraterone and HPBCD, we conclude that abiraterone and HPBCD interact little or noly in these KSD lots. Can be attached.

The peak assignment of the Raman spectrum of the pure abiraterone API (Table 20) was based on the group frequency characteristic of Raman reported in the literature (Long 2004; Stolarczyk et al. 2018). The peak shift of the melt-quenched abiraterone API (Table 21) was caused by the breakdown of hydrogen bonds in the amorphous abiraterone, which changed its chemical environment. No major peak shifts were observed for Lot 1 PM, thus reconfirming that there was no interaction between abiraterone and HPBCD in PM. Among the KSDs, the maximum peak shift was observed in the lot 1 KSD, thus suggesting that the interaction between abiraterone and HPBCD in the lot 1 KSD was the largest. There are peaks related only to the abiraterone API in the 1535 to 1700 cm ^-1 region, and there is no interference by HPBCD. Therefore, we focused on this area. The peak shift associated with the C = C oscillations in the B, D, and pyridine rings of the abiraterone in Lot 1 KSD is large. Therefore, this suggests that these rings interact with HPBCD and are likely to be contained in their hydrophobic pockets. These peak shifts scale from Lot 1 KSD to Lot 3 KSD, ie, as drug loading increases. Therefore, this suggests that in Lot 2 and Lot 3 KSD, the interaction between abiraterone and HPBCD was reduced. For lot 4 and lot 5 KSDs, only small peak shifts were observed due to the C = C oscillations in the B ring. Therefore, this suggests that there is minimal partial interaction between abiraterone and HPBCD in these KSDs. Due to the hydrophilicity of the HPBCD outer surface, it can be assumed that the interaction between the abiraterone in the KSD and the HPBCD outer surface is not large. However, it is still possible that abiraterone-OH and HPBCD-OH are hydrogen bonded when abiraterone is not completely contained within the HPBCD. This abiraterone-free abiraterone is likely to have a smaller apparent water solubility than the abiraterone contained within the HPBCD. Gong and Zhu reported that abiraterone acetate and abiraterone can form a complex with β-cyclodextrin (Gong and Zhu 2013).

Overall, from 1D ¹³ C ss NMR spectroscopy and Raman spectroscopy, all amorphous avilaterons in Lot 1 KSD are either contained or complexed inside the HPBCD, Lot 2 and Lot 3 It is suggested that KSD contains amorphous avilateron partially complexed inside HPBCD, and lot 4 and lot 5 KSD mainly contain crystalline avilateron that has little interaction with HPBCD. Ru. The abiraterone: HPBCD molar ratios for lots 1-5 KSD are 1.0: 2.2, 1.0: 1.0, 1.0: 0.6, 1.0: 0.4, and 1.0: 0.2, respectively. Therefore, as the amount of drug loading increases, the number of HPBCD molecules available to interact with abiraterone decreases, thereby reducing the interaction between abiraterone and HPBCD. Although the stoichiometry of abiraterone: HPBCD in these KSDs cannot be stated based on 1D ss NMR results, it seems that the preferred stoichiometry of abiraterone: HPBCD could be 1: 2. This can be further supported by the theoretical dimensions of abiraterone and HPBCD. The HPBCD has an internal cavity diameter of 0.62-0.78 nm, partially shielded, and its length is 0.79 nm (Szente et al. 2018; Roquette 2006; Tsuchido et al. 2017). Abiraterone is considered a pyridyl derivative of pregnenolone and is reported to have a length of 13 Å, or 1.3 nm (Haider et al. 2010). The kinetic diameter of pyridine is 5.7 Å, or 0.57 nm, and the kinetic diameter of cyclohexane (similar to cyclohexanol of ring A-avilateron) is 0.69 nm (Weng et al. 2015). Therefore, abiraterone can be contained in the HPBCD cavity from either end, but the overall length of abiraterone cannot be covered by a single HPBCD molecule. Therefore, in theory, 2 moles of HPBCD are required to fully contain abiraterone. This is consistent with the results of solid-state interaction tests. This suggests that 10% drug loading lot 1 KSD completely formed an abiraterone complex with HPBCD.

A 2D 13C-1H HETCOR was used to further study the abiraterone-HPBDC interaction with higher resolution. Most recently, this 2D heteronuclear correlation spectroscopy has succeeded in identifying enriched API-polymer interactions in ASD (Lu et al., Mol Pharm, 2019, 16, 6, 2579-2589). ; And Hanada et al., International Journal of Pharmaceutics, Volume 548, Issue 1, 5 September 2018, Pages 571-585). For example, various types of hydrogen bonds, electrostatic interactions, and hydrophobic interactions have been discovered between posaconazole and different polymers, including HPMCAS and HPMCP (Lu et al., 2019). In our previous work, we found that larger energy inputs enhance molecular interactions within the three-component ASD (Hanada et al). In this study, 2D spectra of crystalline abiraterone (black), HPBCD (red), and lot 3 KSD (blue) are shown in Figure 31. The expanded spectrum in the 13C region at 90-160 ppm contains the aromatic peak of abiraterone at 120-150 ppm and the anomeric carbon peak of HPBCD at about 103 ppm (O'Brein et al., Carbohydrate Research, Volume 339, Issue). 1, 2 January 2004, pages 87-96). Abiraterone shows well-separated carbon resonances in the crystal reference (black) and less peaks in KSD due to line broadening and peak overlap. This is in good agreement with the analysis of the 1D 13C spectrum. The HPBCD reference spectrum (red) shows one broad 1H peak that is a proton bound to the anomeric carbon. Interestingly, this anomeric carbon has a new correlation with the proton peak at about 6.4 ppm, which can probably be assigned to the aromatic protons of abiraterone. This new cross-peak suggests that the aromatic region of abiraterone and the anomeric proton of HPBCD interact between molecules.

Example 26: Solution State Phase Solubility Profile Figure 32 shows the phase solubility profile of abiraterone-HPBCD in 0.01N HCl and FaSSIF. In both phases, 0.01N HCl and FaSSIF, the abiraterone solubility increased as the HPBCD concentration increased. In particular, in the HPBCD concentration range of 71.48 μM / mL to 428.88 μM / mL, abiraterone solubility in 0.01N HCl was significantly higher than FaSSIF.

Solution-state phase solubility profiles are usually created to understand the kinetics of drug-CD complex formation for complex preparation by solvent-based methods. However, herein, we have created a solution-state phase solubility profile to understand the effect on KSD elution. In the lysed state, the CD is free solubilized by driving forces such as the release of enthalpy-rich water molecules from the CD cavity, van der Waals interactions, electrostatic interactions, hydrogen bonds, and hydrophobic interactions. Can form complexes with other drugs (Loftsson et al. 2005). Based on the Higuchi and Connors classification, it can be seen that for abiraterone and HPBCD, A-type solution state phase solubility profiles occurred in 0.01N HCl and in FaSSIF medium (Fig. 32) (Loftsson). et al. 2005; Saokham et al. 2018). This means that as the HPBCD concentration increases, the amount of solubilized abiraterone increases. Therefore, upon KSD elution, the resolubilization of unabsorbed abiraterone will depend on the HPBCD concentration. Therefore, maximum viable HPBCD concentration is preferred for abiraterone solubilization.

Furthermore, a large amount of abiraterone solubilization was observed in 0.01N HCl compared to FaSSIF. This is because 0.01N HCl has a higher inherent abiraterone solubility and therefore more abiraterone solubilizes in 0.01N HCl compared to FaSSIF to form a complex with HPBCD. It should be noted that non-ionized drugs usually form more stable complexes with CD than ionized drugs (Loftsson et al. 2005). Since the pKa of abiraterone is 4.81, it will form a more stable complex in FaSSIF (Drugbank 2007).

Example 27: KSD Stability Figure 33 shows an X-ray diffraction pattern of lots 1-3 KSD at 90 ° C and 150 ° C. At both 90 ° C and 150 ° C, lots 1 and 2 KSD showed a complete halo pattern and did not show sharp diffraction peaks corresponding to the pure abiraterone API (Figure 28). Lot 3 KSD showed sharp diffraction peaks corresponding to the pure abiraterone API at both 90 ° C and 150 ° C (Fig. 28). More specifically, it showed characteristic avirateron peaks at 16.65 ° and 19.66 °, but no peak at 8.43 °.

We evaluated KSD stability at high temperatures. Abiraterone in Lot 1 and 2 KSD was found to remain amorphous at both 90 ° C and 150 ° C, whereas Lot 3 KSD showed abiraterone recrystallization at both high temperatures. (Fig. 33). This may be explained on the basis of the solid-state interaction of abiraterone and HPBCD in KSD. Since each molecule of abiraterone is complexed with at least one molecule of HPBCD in lots 1 and 2 KSD, the abiraterone is thermally and kinically stabilized in these KSDs and therefore during heating. Recrystallization is inhibited. In Lot 3 KSD, only a small portion of the abiraterone molecule is complexed with HPBCD, so the free uncomplexed abiraterone molecule recrystallizes upon heating, thereby destabilizing the KSD.

Example 28: In vitro and in vivo performance of KSD Figure 34 illustrates the in vitro non-sync gastric transfer elution profile of pure abiraterone API and lots 1-5 KSD; red region (0.01N HCl) and blue region (FaSSIF). Lots 1-5 KSD showed 15.7-fold, 12.1-fold, 7.2-fold, 5.0-fold, and 3.1-fold enhanced abiraterone elution, respectively, compared to the pure abiraterone API. All KSD lots showed high abiraterone elution in 0.01N HCl compared to FaSSIF. Among the KSDs, the abiraterone elution enhancement trend was Lot 1 KSD> Lot 2 KSD> Lot 3 KSD> Lot 4 KSD> Lot 5 KSD. When integrating the area under the total drug elution curve (AUDC _Total ), the relative AUDC _Total for lots 2-5 KSD was 76.9%, 45.6%, 32.0%, and 19.5%, respectively, compared to lot 1 KSD. there were.

To develop a viable dosage form for abiraterone delivery, the KSD was compressed into an immediate release tablet formulation. 10% drug loading KSD, ie tablet formulation containing lot 1 KSD, 20% drug loading KSD, ie tablet formulation containing lot 2 KSD, 30% drug loading KSD, ie tablet formulation containing lot 3 KSD 3 types were compressed into lot 1 tablet, lot 2 tablet, and lot 3 tablet containing 50.0 mg of avilateron, respectively. All tablets had optimal hardness, assay, purity, acceptable friability, disintegration time, and elution. These tablets were tested and compared to Zytiga® tablets containing 250 mg abiraterone acetate.

FIG. 35 shows the in vivo mean plasma concentration v / s time profile from oral dosing of Zytiga® and lots 1-3 tablets in fasted non-naive male beagle dogs. Table 22 lists the pharmacokinetic (PK) parameters. Zytiga® showed a highly variable plasma concentration v / s time profile among all three animals. One of the animals in the Zytiga® test group (# JA0167) (individual animal data not shown) had a maximum abiraterone plasma concentration, ie 78.50 ng / mL C _max per hour, 10 hours. Shows another C _max of 115.00 ng / mL, which contributed to the high drug exposure of Zytiga®, ie AUC _{(0-48 hr)} . Lot 1-3 tablets showed small drug exposure variability compared to Zytiga®, ie, a small% CV of AUC _(0-48hr) . Zytiga® showed a very large variation of 121.39% for T _max . Overall, lots 1-3 tablets were able to enhance the bioavailability of abiraterone 3.9-fold, 2.7-fold, and 1.7-fold, respectively, compared to Zytiga®.

(Table 22) Results from in vivo pharmacokinetic (PK) studies in male beagle dogs

In FIG. 36, we plotted the in vitro percent relative and in vivo percent relative performance of KSDs with varying drug loadings. As the drug loading of KSD increased, both in vitro performance, i.e., performance in terms of AUDC _Total and in vivo performance in terms of AUC _(0-48hr) decreased. Interestingly, the relative performance trends for both in vitro and in vivo studies were similar.

In vitro elution tests (Fig. 34) showed that all KSDs enhanced abiraterone elution. Relative in vitro elution performance of KSD decreased as drug loading increased. This may be due to a decrease in abiraterone-HPBCD complex formation, and thus a decrease in abiraterone solubility enhancement and an increase in drug loading. It should be noted that both increased and decreased elution performance can occur with increased drug loading, which is specific to the drug, CD type, preparation method, and elution medium (M Badr). -Eldin, A Ahmed, and R Ismail, 2013; Semalty et al., 2014; Loh, Tan, and Peh, 2016). As seen in the lysed phase solubility profile, KSD also showed abiraterone elution in 0.01N HCl compared to FaSSIF medium. In the FaSSIF medium, lot 1 KSD was eluted more than other KSDs. This is because in Lot 1 KSD, the abiraterone precipitation rate is small because the abiraterone complex is completely formed. Overall, 10% drug loading lot 1 KSD showed maximum in vitro avilateron elution enhancement.

In vivo pharmacokinetic studies (FIG. 35 and Table 22) found that all KSD tablets enhanced abiraterone exposure compared to Zytiga® on a dose-adjusted basis.

Lot 1 and 2 tablets at a dose of about 1/5 showed a higher C _max than Zytiga®. On a dose-adjusted basis, Lot 1, Lot 2, and Lot 3 KSDs exhibit a larger AUC _(0-48hr) than Zytiga®, so all three KSD tablets enhance the bioavailability of abiraterone. Was done. As the amount of drug loading in KSD from lots 1-3 tablets increased, C _max , AUC _(0-48hr) , and thus the enhancement of bioavailability decreased. This may be due to decreased abiraterone-HPBCD interactions, decreased elution and increased drug loading. It can also be inferred that HPBCD did not adversely affect abiraterone elution, as one lot tablet contained the highest amount of HPBCD among KSD tablets but had the highest abiraterone exposure. KSD tablets were used to reduce drug exposure variability, which improved abiraterone pharmacokinetics. Overall, 10% drug loading lot 1 KSD showed the best in vivo pharmacokinetic performance.

From FIG. 36, it can be seen that there was a good correlation between in vitro elution performance and in vivo pharmacokinetic performance for KSD and its tablets. From FIG. 36, it can be inferred that the 5% drug loading KSD may have shown even better performance. However, this may not be the case, as abiraterone is fully complexed with HPBCD at 10% drug loading and the addition of HPBCD may not increase performance proportionally. In addition, 5% drug loading KSD will cause the problem of pill burden. Therefore, a 10% drug loading KSD may be optimal.

As shown in Examples 22-28, we developed KSDs with 10-50% w / w drug loading and used these KSDs for X-ray diffraction and modulated scanning calorimetry. ) Was used for analysis. We have found that KSDs containing 10-30% drug loading are amorphous. Solid-state interaction studies using nuclear magnetic resonance spectroscopy and Raman spectroscopy revealed that maximal avilateron-HPBCD interactions occurred inside a 10% drug-loading KSD. This is probably due to the abiraterone: HPBCD molar ratio of 1: 2 in this KSD. The solution-state phase solubility profile of abiraterone-HPBCD was A-type. This means that the amount of solubilized abiraterone is directly proportional to the HPBCD concentration. At high temperatures, the 10% drug-loading KSD and the 20% drug-loading KSD were chemically stable, whereas the 30% drug-loading KSD showed abiraterone recrystallization. In vitro elution performance and in vivo pharmacokinetic performance decreased as drug loading increased in KSD. This may be due to a decrease in abiraterone-HPBCD interaction and an increase in drug loading. Overall, the 10% drug-loading KSD showed a 15.7-fold enhanced elution compared to pure abiraterone and a 3.9-fold enhanced bioavailability compared to the commercially available abiraterone acetate tablets-ZYTIGA®. rice field. Therefore, KinettiSol®, a high energy solvent-free technology, has the potential to form a 10% abiraterone-HPBCD complex that functions optimally in KSD in terms of improving in vitro and in vivo performance.

Examples 22-28 show that KinettiSol® is an efficient high energy solvent-free technique for making abiraterone-HPBCD compositions with 10% -50% drug loading. As drug loading increases, the abiraterone-HPBCD interaction within the KSD decreases, the abiraterone elution enhancement decreases, and the abiraterone bioavailability enhancement decreases. The 10% drug loading KSD is stoichiometrically balanced to fully interact with abiraterone for the purpose of maximizing in vitro and in vivo performance. Therefore, 10% drug loading KSD has the potential to improve therapeutic outcomes in patients with prostate cancer.

The above disclosures include various examples of pharmaceutical formulations, final solid dosage forms, methods of forming pharmaceutical formulations, and methods of administering pharmaceutical formulations. All of these various embodiments can be combined with each other, even if they are not explicitly combined in the present disclosure, unless they are clearly mutually exclusive. For example, a particular pharmaceutical formulation may contain a more generally specified amount of the ingredient and may be administered by any method described herein.

In addition, the materials of various embodiments are discussed herein, by way of example, by using the term "including" or "such-as" as suitable materials. Identified as a material contained within the types of materials described more broadly. All such terms are used in a non-limiting manner, as other materials exemplified, but not explicitly specified, contained within the same general type may also be used in the present disclosure.

The subject matter disclosed above must be considered as exemplary and not limiting, and the claims of the attachment are within the true spirit and scope of this disclosure. It is intended to cover all such modifications, enhancements, and other aspects. Accordingly, to the maximum extent permitted by law, the scope of the present disclosure shall be determined by the broadest acceptable interpretation of the claims and their equivalents below and may be limited or limited by the detailed description described above. It shall not be.

References Various patents, patent applications, and publications are cited herein, including: All of these contents are incorporated herein in their entirety.

Claims (140)

A pharmaceutical preparation containing abiraterone and a cyclic oligomer excipient. The pharmaceutical preparation according to claim 1, wherein the abiraterone contains an amorphous abiraterone. The pharmaceutical preparation according to claim 2, wherein the abiraterone contains less than 5% crystalline abiraterone. The pharmaceutical preparation according to claim 1, wherein the abiraterone contains at least 99% of the abiraterone. Avilaterone has the following structural formula:

The pharmaceutical preparation according to claim 1, which comprises at least 99% of abiraterone having. The pharmaceutical preparation according to claim 1, wherein the abiraterone contains at least 99% of the abiraterone salt. The pharmaceutical preparation according to claim 1, wherein the abiraterone contains at least 99% of the abiraterone ester. Avila terron ester has the following structural formula:

7. The pharmaceutical preparation according to claim 7, which comprises abiraterone acetate having the above. The pharmaceutical preparation according to claim 1, wherein the abiraterone contains at least 99% of the abiraterone solvate compound. The pharmaceutical preparation according to claim 1, wherein the abiraterone contains at least 99% of the abiraterone hydrate. The pharmaceutical preparation according to claim 1, which comprises 10 mg, 25 mg, 50 mg, 70 mg, 75 mg, 100 mg, or 125 mg of amorphous avilateron. Achieves the same or greater therapeutic effect, bioavailability, C _min , C _max , or T _max in patients with 250 mg, 500 mg, or 1000 mg of crystalline abiraterone or crystalline abiraterone acetate when taken on an empty stomach. The pharmaceutical formulation according to claim 1, which comprises a sufficient amount of amorphous abiraterone. The pharmaceutical preparation according to claim 1, which comprises 50 mg of amorphous avirateron. Sufficient amount to achieve the same or greater therapeutic effect, bioavailability, C _min , C _max , or T _max in patients with 500 mg of crystalline abiraterone or crystalline abiraterone acetate when taken on an empty stomach. The pharmaceutical preparation according to claim 1, which comprises amorphous abiraterone. The pharmaceutical preparation according to claim 1, which comprises 50 mg or 70 mg of amorphous avirateron. Enough to achieve the same or greater therapeutic effect, bioavailability, C _min , C _max , or T _max in patients with 500 mg or 1,000 mg of crystalline abiraterone or crystalline abiraterone acetate when taken on an empty stomach. The pharmaceutical preparation according to claim 1, which comprises an amount of amorphous abiraterone. The pharmaceutical preparation according to claim 1, wherein the abiraterone and the cyclic oligomer are present in a molar ratio of 1: 0.25 to 1:25. The pharmaceutical preparation according to claim 1, wherein the abiraterone and the cyclic oligomer are present in a molar ratio of at least 1: 2. The pharmaceutical preparation according to claim 1, which comprises 1% by weight to 50% by weight of amorphous avirateron. The pharmaceutical preparation according to claim 1, which comprises at least 10% by weight of amorphous avirateron. The pharmaceutical preparation according to claim 1, wherein the cyclic oligomer excipient comprises a cyclic oligosaccharide or a cyclic oligosaccharide derivative. The pharmaceutical preparation according to claim 21, wherein the cyclic oligosaccharide or the cyclic oligosaccharide derivative comprises a cyclodextrin or a cyclodextrin derivative. 22. The pharmaceutical preparation according to claim 22, wherein the cyclodextrin derivative comprises hydroxypropyl β cyclodextrin. 22. The pharmaceutical preparation according to claim 22, wherein the cyclodextrin derivative comprises sodium (Na) sulfo-butyl ether β-cyclodextrin. 22. The pharmaceutical preparation according to claim 22, wherein the cyclodextrin derivative contains a sulfobutyl ether functional group. 22. The pharmaceutical preparation according to claim 22, wherein the cyclodextrin derivative contains a methyl group. The pharmaceutical preparation according to claim 1, which comprises 50% by weight to 99% by weight of a cyclic oligomer excipient. The pharmaceutical preparation according to claim 1, which comprises at least 60% by weight of a cyclic oligomer excipient. The pharmaceutical formulation according to claim 1, further comprising an additional excipient. 29. The pharmaceutical preparation according to claim 29, wherein the cyclic oligomer excipient is the primary excipient. 29. The pharmaceutical formulation of claim 29, wherein the further excipient is a primary excipient. 30. The pharmaceutical formulation of claim 30, wherein the further excipient is a secondary excipient. 29. The pharmaceutical formulation of claim 29, wherein the further excipient is a polymeric excipient. 33. The pharmaceutical formulation of claim 33, wherein the polymer excipient is water soluble. 33. The pharmaceutical formulation of claim 33, wherein the polymer excipient comprises a nonionic polymer. 33. The pharmaceutical formulation of claim 33, wherein the polymer excipient comprises an ionic polymer. 33. The pharmaceutical formulation of claim 33, wherein the polymeric excipient comprises hydroxypropylmethylcellulose acetate succinate. 37. The pharmaceutical formulation of claim 37, wherein the hydroxypropylmethylcellulose acetate succinate has a 5-14% acetate substitution and a 4-18% succinate substitution. 38. The pharmaceutical formulation of claim 38, wherein the hydroxypropylmethylcellulose acetate succinate has a 10-14% acetate substitution and a 4-8% succinate substitution. 39. The pharmaceutical formulation of claim 39, wherein the hydroxypropylmethylcellulose acetate succinate has a 12% acetate substitution and a 6% succinate substitution. 29. The pharmaceutical formulation of claim 29, comprising an additional excipient of 1% to 49% by weight. 29. The pharmaceutical formulation of claim 29, comprising an additional excipient of 10% by weight or less. The pharmaceutical formulation according to claim 1, further comprising a glucocorticoid replacement API. 43. The pharmaceutical formulation of claim 43, wherein the glucocorticoid replacement API comprises prednisone, methylprednisolone, prednisolone, methylprednisolone, dexamethasone, or a combination thereof. ₁ . pharmaceutical formulation. 17 _.. Pharmaceutical formulation. The pharmaceutical product of claim 1, wherein the pharmaceutical product comprises an amount of amorphous abiraterone sufficient to achieve a C _max variation reduction of at least 6% in the patient with an equal amount of crystalline abiraterone or crystalline abiraterone acetate when ingested on an empty stomach. Formulation. 17 _.. Pharmaceutical formulation. Amorphous abiraterone in an amount sufficient to achieve a C _max variation reduction of at least 25% of an equal amount of crystalline abiraterone or crystalline abiraterone acetate when ingested on an empty stomach in a patient when ingested in a feeding condition. The pharmaceutical preparation according to claim 1, which comprises Ron. Sufficient amount to achieve an AUC _0-t variability reduction of at least 23% of the equivalent amount of crystalline avilateron or crystalline avilatelate acetate when ingested on an empty stomach in a patient when ingested in a fed state. The pharmaceutical preparation according to claim 1, which comprises amorphous avilateron. The pharmaceutical according to claim 1, which comprises an amount of amorphous avilateron sufficient to achieve a Cmax variation of less than 30% when ingested in a fasted state as compared to a Cmax when ingested in a fasted state. pharmaceutical formulation. Enough amounts of amorphous avilateron to achieve an AUC _0-t variation of less than 10% in patients when ingested in a fasted state compared to AUC _0-t when ingested in a fasted state. The pharmaceutical preparation according to claim 1, which comprises. Containing sufficient amounts of amorphous avilateron to achieve an average Cmin of at least 35 ng / mL in the human patient population when administered once daily, twice daily, three times daily, or four times daily. The pharmaceutical preparation according to claim 1. Increased therapeutic effect, bioavailability, Cmin, or Cmax compared to equal or greater amounts of crystalline abiraterone or equal or greater amounts of crystalline abiraterone acetate when ingested in a fasted state. The pharmaceutical formulation according to claim 1, comprising an amount of amorphous abiraterone sufficient to achieve in patients with metastatic castration-resistant prostate cancer and primary resistance. Increased therapeutic effect, bioavailability, Cmin, or Cmax compared to an equal or greater amount of crystalline abiraterone or an equal or greater amount of crystalline abiraterone acetate when ingested in a fasted state. The pharmaceutical formulation according to claim 1, comprising an amount of amorphous abiraterone sufficient to achieve in patients with metastatic castration-resistant prostate cancer and acquired resistance. Increased therapeutic effect, bioavailability, Cmin, or Cmax compared to an equal or greater amount of crystalline abiraterone or an equal or greater amount of crystalline abiraterone when ingested in a fasted state. The pharmaceutical formulation according to claim 1, which comprises an amount of amorphous abiraterone sufficient to achieve in a patient with triple negative breast cancer. Increased therapeutic effect, bioavailability, Cmin, or Cmax compared to an equal or greater amount of crystalline abiraterone or an equal or greater amount of crystalline abiraterone acetate when ingested in a fasted state. The pharmaceutical formulation according to claim 1, comprising an amount of amorphous abiraterone sufficient to achieve in patients with non-metastatic castration-resistant prostate cancer. A tablet for oral administration, which comprises the pharmaceutical preparation according to any one of claims 1 to 57. 58. The tablet according to claim 58, further comprising a coating. The tablet according to claim 59, wherein the coating comprises a glucocorticoid supplement API. The tablet according to claim 60, wherein the glucocorticoid replacement API comprises prednisone, methylprednisolone, prednisolone, methylprednisolone, dexamethasone, or a combination thereof. 58. The tablet of claim 58, comprising an external phase comprising an additional amount of a cyclic oligomeric excipient. 58. The tablet of claim 58, comprising an external phase comprising at least one additional excipient. 58. The tablet according to claim 58, which comprises an increasing concentration polymer. The tablet according to claim 64, wherein the increasing concentration polymer comprises hydroxypropylmethylcellulose acetate succinate. 58. The tablet of claim 58, comprising an external phase comprising at least one additional drug release modified excipient. 58. The tablet of claim 58, comprising an external phase comprising one or more hydrogel-forming excipients. 67. The tablet according to claim 67, comprising an external phase comprising a combination of polyethylene oxide and hydroxypropylmethyl cellulose. Including a step of blending crystalline avilateron and a cyclic oligomer excipient in a thermodynamic mixer at a temperature equal to or less than 200 ° C. for less than 300 seconds to form an amorphous avilateron and a cyclic oligomer excipient. A method of forming a pharmaceutical formulation. The method according to claim 69, wherein the pharmaceutical product is the pharmaceutical product according to any one of claims 1 to 57. 39. The method of claim 69, further comprising blending at least one additional excipient with crystalline abiraterone and a cyclic oligomeric excipient. 39. The method of claim 69, wherein blending in a thermodynamic mixer does not cause substantial thermal decomposition of abiraterone. 39. The method of claim 69, wherein blending in a thermodynamic mixer does not cause substantial thermal decomposition of the cyclic oligomeric excipient. 17. The method of claim 71, wherein blending in a thermodynamic mixer does not cause substantial thermal decomposition of the further excipient. It contains a hot melt extrusion that is treated with crystalline avilateron and a cyclic oligomer excipient to form an amorphous avilateron and a cyclic oligomer excipient, wherein the avilateron is substantially not thermally decomposed, pharmaceuticalally. How to form a formulation. The method according to claim 75, wherein the pharmaceutical product is the pharmaceutical product according to any one of claims 1 to 57. 17. The method of claim 75, further comprising treating at least one additional excipient with crystalline abiraterone and a cyclic oligomeric excipient. 75. The method of claim 75, wherein the melt treatment does not cause substantial thermal decomposition of the cyclic oligomeric excipient. 17. The method of claim 77, wherein the melt treatment does not cause substantial thermal decomposition of the additional excipient. It comprises a step of dissolving crystalline avilateron and a cyclic oligomer excipient in a common organic solvent to form a dissolved mixture, and a step of spray-drying the dissolved mixture to form an amorphous avilateron and a cyclic oligomer excipient. A method of forming a pharmaceutical formulation. The method according to claim 80, wherein the pharmaceutical product is the pharmaceutical product according to any one of claims 1 to 57. 80. The method of claim 80, further comprising the steps of dissolving at least one additional excipient with crystalline abiraterone and cyclic oligomeric excipients, as well as spray drying. 80. The method of claim 80, wherein spray drying does not cause substantial thermal decomposition of abiraterone. 80. The method of claim 80, wherein spray drying does not cause substantial thermal decomposition of the cyclic oligomeric excipient. 82. The method of claim 82, wherein spray drying does not cause substantial thermal decomposition of the additional excipient. Amorphous avilateron and cyclic oligomers are formed by combining avilateron and cyclic oligomer excipients by methods including wet mass extrusion, high intensity mixing, high intensity mixing with solvent, ball milling, or ball milling with solvent. A method of forming a pharmaceutical product, which comprises the steps of forming a pharmaceutical product. Treatment of prostate cancer in a patient comprising the step of administering the pharmaceutical preparation according to any one of claims 1 to 57 or the tablet according to any one of claims 58 to 68 to a patient having prostate cancer. Method. Patients with cast-resistant prostate cancer, metastatic cast-resistant prostate cancer, metastatic prostate cancer, locally advanced prostate cancer, recurrent prostate cancer, non-metastatic cast-resistant prostate cancer, or other high-risk prostate cancer 8. The method of claim 87. 17. The method of claim 87, wherein the patient has previously been treated with chemotherapy. 89. The method of claim 89, wherein the chemotherapy comprises docetaxel. 87. The method of claim 87, wherein the patient has previously been treated with enzalutamide. 17. The method of claim 87, wherein the patient has previously experienced a sub-optimal response to crystalline abiraterone acetate. 87. The method of claim 87, wherein the pharmaceutical product or tablet is administered to the patient in combination with androgen deprivation therapy. 87. The method of claim 87, wherein the pharmaceutical product or tablet is administered to the patient in combination with the glucocorticoid replacement API. 87. The method of claim 87, wherein the pharmaceutical product or tablet is administered once daily. 87. The method of claim 87, wherein the pharmaceutical product or tablet is administered twice daily, three times daily, or four times daily. Compared to the dose of abiraterone acetate in weight units, which contains amorphous abiraterone and is sufficient to achieve the same therapeutic effect, bioavailability, C _min , C _max , or T _max . 87. The method of claim 87, wherein the dose of abiraterone is administered in as little as a weight unit. 87. The method of claim 87, wherein the patient has metastatic castration-resistant prostate cancer and primary resistance to treatment with crystalline abiraterone or crystalline abiraterone acetate. 87. The method of claim 87, wherein the patient has metastatic castration-resistant prostate cancer and acquired resistance to treatment with crystalline abiraterone or crystalline abiraterone acetate. A method for treating breast cancer in a patient comprising the step of administering the pharmaceutical preparation according to any one of claims 1 to 57 or the tablet according to any one of claims 58 to 68 to a patient having breast cancer. The method of claim 100, wherein the patient has molecular apocrine breast cancer or triple negative breast cancer. The method of claim 100, wherein the patient has previously been treated with chemotherapy. 10. The method of claim 102, wherein the chemotherapy comprises docetaxel. The method of claim 100, wherein the patient has previously been treated with enzalutamide. The method of claim 100, wherein the patient has previously experienced a suboptimal response to crystalline abiraterone acetate. The method of claim 100, wherein the pharmaceutical product or tablet is administered to the patient in combination with androgen deprivation therapy. The method of claim 100, wherein the pharmaceutical product or tablet is administered to the patient in combination with the glucocorticoid replacement API. The method of claim 100, wherein the pharmaceutical product or tablet is administered once daily. The method of claim 100, wherein the pharmaceutical product or tablet is administered twice daily, three times daily, or four times daily. Compared to the dose of abiraterone acetate in weight units, which contains amorphous abiraterone and is sufficient to achieve the same therapeutic effect, bioavailability, C _min , C _max , or T _max . 100. The method of claim 100, wherein the dose of abiraterone is administered in as little as a weight unit. Treating salivary gland cancer in a patient comprising the step of administering the pharmaceutical preparation according to any one of claims 1 to 57 or the tablet according to any one of claims 58 to 68 to a patient having salivary gland cancer. Method. 11. The method of claim 111, wherein the patient has relapsed and / or metastatic salivary gland cancer. 11. The method of claim 111, wherein the patient has previously been treated with chemotherapy. The method of claim 113, wherein the chemotherapy comprises docetaxel. The method of claim 113, wherein the patient has previously been treated with enzalutamide. 13. The method of claim 113, wherein the patient has previously experienced a suboptimal response to crystalline abiraterone acetate. 13. The method of claim 113, wherein the pharmaceutical product or tablet is administered to the patient in combination with androgen deprivation therapy. 13. The method of claim 113, wherein the pharmaceutical product or tablet is administered to the patient in combination with the glucocorticoid replacement API. 13. The method of claim 113, wherein the pharmaceutical product or tablet is administered once daily. 13. The method of claim 113, wherein the pharmaceutical product or tablet is administered twice daily, three times daily, or four times daily. Compared to the dose of abiraterone acetate in weight units, which contains amorphous abiraterone and is sufficient to achieve the same therapeutic effect, bioavailability, C _min , C _max , or T _max . The method of claim 113, wherein the dose of abiraterone is administered in as little as a weight unit. Treatment of cancer in a patient comprising the step of administering the pharmaceutical preparation according to any one of claims 1 to 57 or the tablet according to any one of claims 58 to 68 to a patient having androgen-sensitive cancer. Method. The method of claim 122, wherein the patient has previously been treated with chemotherapy. The method of claim 123, wherein the chemotherapy comprises docetaxel. 23. The method of claim 123, wherein the patient has previously been treated with enzalutamide. 23. The method of claim 123, wherein the patient has previously experienced a suboptimal response to crystalline abiraterone acetate. 23. The method of claim 123, wherein the pharmaceutical product or tablet is administered to the patient in combination with androgen deprivation therapy. 23. The method of claim 123, wherein the pharmaceutical product or tablet is administered to the patient in combination with the glucocorticoid replacement API. 23. The method of claim 123, wherein the pharmaceutical product or tablet is administered once daily. 23. The method of claim 123, wherein the pharmaceutical product or tablet is administered twice daily, three times daily, or four times daily. Compared to the dose of abiraterone acetate in weight units, which contains amorphous abiraterone and is sufficient to achieve the same therapeutic effect, bioavailability, C _min , C _max , or T _max . 123. The method of claim 123, wherein the dose of abiraterone is administered in as little as a weight unit. The pharmaceutical preparation according to claim 1, which comprises an inclusion complex containing an amorphous avilateron and a cyclic oligomer excipient. 13. The pharmaceutical formulation of claim 132, comprising amorphous avilaterons up to 30% by weight, 20% by weight, or 10% by weight. 13. The pharmaceutical formulation of claim 132, comprising up to 10% by weight amorphous avilateron. 13. The pharmaceutical formulation of claim 132, which is formed by a method comprising a thermodynamic formulation. 13. Pharmaceutical formulation. The pharmaceutical product is heated to a temperature up to 90% of the melting point of crystalline abiraterone and
Less than 10%, less than 9%, less than 8%, less than 7%, less than 6%, less than 5%, less than 4%, less than 3%, 2% of abiraterone in response to cooling the pharmaceutical product to room temperature 13. The pharmaceutical formulation of claim 132, wherein less than, less than 1%, or less than 0.1% is crystalline. Less than 10%, less than 9%, less than 8%, less than 7%, less than 6%, less than 5%, less than 4%, less than 3%, less than 2%, less than 1%, or less than 0.1% of crystalline abiraterone However, the pharmaceutical preparation according to claim 137, which is confirmed by a method comprising X-ray diffraction. Proven by elution with 0.01N HCl and at least one of the bio-related media selected from simulated gastric juice (SGF), fasting simulated intestinal juice (FaSSIF), and fasting simulated intestinal juice (FeSSIF). 13. The pharmaceutical formulation according to claim 132, which has an increased elution in the gastrointestinal tract of the patient at least 13 to 17-fold as compared to the pharmaceutical formulation containing pure crystalline avilateron. 23. The pharmaceutical formulation according to claim 132, which has a 4-fold increase in the bioavailability of abiraterone in a patient as compared to a higher amount of crystalline abiraterone or crystalline abiraterone acetate when ingested on an empty stomach.

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